@article {pmid42893563,
year = {2026},
author = {Altas, B and Georgiou, P and Onisiforou, A},
title = {AI-bioinformatics synergy for precision medicine in brain diseases: integrating radiomics and multi-omics data.},
journal = {Briefings in bioinformatics},
volume = {27},
number = {5},
pages = {},
pmid = {42893563},
issn = {1477-4054},
support = {//IDSA Foundation/ ; },
mesh = {Humans ; Radiomics ; *Precision Medicine/methods ; Multiomics ; *Computational Biology/methods ; *Artificial Intelligence ; *Brain Diseases/diagnostic imaging/genetics/metabolism ; Genomics ; Proteomics ; Brain Neoplasms/diagnostic imaging ; },
abstract = {The convergence of artificial intelligence (AI) and bioinformatics is reshaping the landscape of precision medicine in brain diseases, particularly in neurological diseases and brain tumors. Despite advances in both fields, the combined application of radiomics and multi-omics fusion remains underutilized, even though integrative frameworks are essential for addressing the complexity and heterogeneity of imaging and molecular data. This review examines how integrative AI-bioinformatics frameworks enable the fusion of radiomics with genomics, transcriptomics, proteomics, and other omics modalities to more comprehensively model disease complexity. Leveraging deep learning, graph neural networks, and advanced representation learning, these multimodal systems facilitate biomarker discovery, patient stratification, and personalized treatment strategies. We critically evaluate key challenges including data heterogeneity, limited interpretability, and barriers to clinical validation, and highlight emerging solutions aimed at enhancing reproducibility and translational readiness. Case studies in gliomas, Alzheimer's disease, and multiple sclerosis illustrate the clinical utility of unified imaging-omics architectures. Ultimately, this review positions radiomics and multi-omics integration as a foundational approach for the next generation of precision medicine in brain diseases by bridging the gap between computational innovation and clinical application.},
}

Humans
Radiomics
*Precision Medicine/methods
Multiomics
*Computational Biology/methods
*Artificial Intelligence
*Brain Diseases/diagnostic imaging/genetics/metabolism
Genomics
Proteomics
Brain Neoplasms/diagnostic imaging

@article {pmid42894266,
year = {2026},
author = {Hasegawa, C and Doi, Y and Hirano, T and Shirakawa, M and Tsuchiya, S and Yoshitsugu, H and Furihata, K and Miller, C and Singh, S and Cabalu, T and Yee, KL and Bueters, T and Alexopoulou, Z},
title = {A Phase 1 Study of MK-1942, a Negative Allosteric Modulator of mGluR2, in Healthy Japanese to Flexibly Assess Factors Including CYP2C19 Phenotype.},
journal = {Clinical and translational science},
volume = {19},
number = {11},
pages = {e70748},
pmid = {42894266},
issn = {1752-8062},
support = {//Merck Sharp & Dohme LLC, a subsidiary of Merck & Co. Inc., Rahway, New Jersey, USA/ ; },
mesh = {Adult ; Female ; Humans ; Male ; Middle Aged ; Young Adult ; Administration, Oral ; Allosteric Regulation/drug effects ; Area Under Curve ; *Cytochrome P-450 CYP2C19/genetics/metabolism ; Double-Blind Method ; Healthy Volunteers ; Japan ; Phenotype ; *Receptors, Metabotropic Glutamate/metabolism/antagonists & inhibitors ; East Asian People/genetics ; },
abstract = {MK-1942 is a negative allosteric modulator of the metabotropic glutamate receptor 2 that was investigated for the treatment of Alzheimer's disease and depression. Nonclinical studies with recombinant human CYPs and genotyped human hepatocytes suggested that CYP2C19 is involved in the metabolism of MK-1942. Given the high incidence of different CYP2C19 polymorphisms in the Japanese population, a Phase 1 single and multiple dose study in healthy Japanese participants provided an opportunity to determine the involvement of CYP2C19 phenotype on the clinical PK of MK-1942. Also, since a first-in-human study in non-Japanese showed a decrease in exposures after administration with high-fat meal, we further tested an effect of low-fat meal on PK in the Japan study. The study was designed with flexibility which enabled dose selection for the multiple dose panels, based on the totality of safety and PK data. Oral administration of single and multiple doses of MK-1942 in Japanese participants was generally well tolerated. AUC0-inf was comparable between fasted and fed (low-fat meal) state. Following a single dose of MK-1942, AUC0-inf was ~70% increased in CYP2C19 poor metabolizer (PM) vs. extensive metabolizer (EM). Therefore, a decision was made to test the multiple dose separately for each CYP2C19 phenotype, rather than grouping them into a single panel. As opposed to the expectation from the single dose result, steady state exposures were similar among CYP2C19 phenotypes. These data supported the subsequent global Phase 2 study to permit a low-fat meal around dosing and no dose adjustment for any CYP2C19 phenotype.},
}

Adult
Female
Humans
Male
Middle Aged
Young Adult
Administration, Oral
Allosteric Regulation/drug effects
Area Under Curve
*Cytochrome P-450 CYP2C19/genetics/metabolism
Double-Blind Method
Healthy Volunteers
Japan
Phenotype
*Receptors, Metabotropic Glutamate/metabolism/antagonists & inhibitors
East Asian People/genetics

@article {pmid42894468,
year = {2026},
author = {Markus, HS},
title = {Vascular dementia and vascular cognitive impairment-current treatments and future prospects.},
journal = {International journal of stroke : official journal of the International Stroke Society},
volume = {21},
number = {9},
pages = {1200-1210},
pmid = {42894468},
issn = {1747-4949},
mesh = {Humans ; *Dementia, Vascular/therapy/physiopathology ; *Cognition Disorders/therapy/etiology ; },
abstract = {Vascular cognitive impairment (VCI) and vascular dementia (VaD) represent a substantial and growing global health burden, yet remain under-recognized and comparatively under-researched. Two broad categories are post-stroke cognitive impairment, and VCI secondary to chronic cerebrovascular disease of which the most common cause is cerebral small vessel disease (SVD). In addition, cerebrovascular pathology frequently coexists with Alzheimer's disease (AD), increasing the probability that AD pathology will manifest as clinical dementia. Current management focuses primarily on prevention through modification of cardiovascular risk factors and lifestyle interventions. Intensive blood-pressure control has shown the strongest evidence, reducing future all-cause dementia while slowing progression of white-matter abnormalities. Multidomain lifestyle interventions incorporating exercise, diet, cognitive training, and vascular risk monitoring may also preserve cognition, although results across trials remain variable. In established VCI and VaD, treatment options are limited; cholinesterase inhibitors and memantine lack convincing evidence of benefit, and no pharmacological therapy has definitively demonstrated symptomatic improvement or delayed disease progression. Advances in understanding SVD and VCI pathophysiology are, however, identifying promising therapeutic targets. Emerging evidence highlights endothelial dysfunction, impaired cerebral autoregulation, increased blood-brain barrier permeability, inflammation, and glymphatic dysfunction as possible mechanisms underlying SVD. Current trials are evaluating treatment approaches based on this framework including cerebral vasodilators such as cilostazol, isosorbide mononitrate and phosphodiesterase-5 inhibitors, anti-inflammatory therapies, glucagon-like peptide-1 receptor agonists, remote ischemic conditioning, and strategies targeting glymphatic function. Improved mechanistic understanding, appropriately targeted interventions, and adequately powered long-term clinical trials are required to translate these emerging approaches into effective treatments for VCI and VaD.},
}

Humans
*Dementia, Vascular/therapy/physiopathology
*Cognition Disorders/therapy/etiology

@article {pmid42895147,
year = {2026},
author = {Chaudhary, S and Dhankhar, S and Saini, M and Singh, TG and Chauhan, S and Kumar, V},
title = {Mechanistic Evaluation of Psilocybin in Neurodegenerative Disorders: Relevance of 5-HT2A Receptors and Downstream Pathways.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273491538261009064612},
pmid = {42895147},
issn = {1996-3181},
abstract = {More than fifty million individuals worldwide are experiencing neurodegenerative disorders, which include Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, and frontotemporal dementia. These disorders have a significant role in the gradual degradation of cognition and motor skills. Most current treatment approaches have little effect on changing the course of the disease and are largely symptomatic. Psilocybin, a naturally occurring tryptamine alkaloid from psilocybin mushrooms, has become a promising medicinal agent because of its hallucinogenic, neuroprotective, and neuroplastic properties. After being metabolically transformed into its active form, psilocin, it primarily activates serotonin 5-HT2A receptors. This modulates glutamatergic neurotransmission and neurotrophic signaling pathways such as BDNF/TrkB and mTOR, which regulate synaptic remodeling, dendritic complexity, neurogenesis, neuroinflammatory response, and default mode network connectivity, all of which are linked to depression and dementia. Preclinical research studies demonstrate that psilocybin increases hippocampal plasticity, restores dendritic complexity, lowers proinflammatory cytokine levels, and promotes fear extinction in experimental models of stress, ischemic stroke, and neurodegeneration. Emerging clinical studies also indicate that individuals with moderate cognitive impairment, early-onset Alzheimer's disease, and Parkinson's disease may see long-term decreases in anxiety and depression as well as improvements in cognitive function, frequently after a single dose administration. Additionally, psilocybin has demonstrated promise in treating mental comorbidities that often accompany neurodegenerative illness, such as treatment-resistant depression, drug use disorders, and obsessive-compulsive disorder. However, there are still significant obstacles to overcome, such as optimizing dosing schedules, assessing safety issues such as temporary perceptual abnormalities and cardiovascular consequences, and translating preclinical results into extensive phase -III clinical studies. This review incorporates the most recent data on psilocybin's chemistry, pharmacology, metabolism, and mechanistic actions; it highlights the drug's therapeutic potential across a variety of neurodegenerative diseases and emphasizes the necessity of carefully planned randomized controlled trials to determine clinical efficacy, long-term safety, and its place in multimodal treatment approaches.},
}

@article {pmid42895489,
year = {2026},
author = {Liang, X and Jiang, C and Zhug, H and Sun, Y and Tu, S and Kang, J},
title = {Deep Cervical Lymphaticovenous Anastomosis (LVA) for Alzheimer's Disease: A Case Report.},
journal = {Journal of perianesthesia nursing : official journal of the American Society of PeriAnesthesia Nurses},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jopan.2026.08.005},
pmid = {42895489},
issn = {1532-8473},
abstract = {This case report describes the short-term observed clinical course of a 65-year-old patient with Alzheimer's disease (AD) who underwent deep cervical lymphaticovenous anastomosis (LVA) under general anesthesia, and summarizes the perianesthesia nursing care provided before, during, and after anesthesia. Neuropsychological assessments showed limited changes in cognitive scores at 1 month after surgery, including a 1-point increase in MMSE and a 1-point decrease in ADAS-Cog, while ADCS-ADL declined. The NPI score decreased from 21 preoperatively to 0 on postoperative day 3 and remained lower than baseline, with a score of 2 at 1 month. Given the single-case design, short follow-up period, and lack of a control condition, these observations should be interpreted cautiously and cannot establish treatment efficacy. Deep cervical LVA may warrant further investigation as an exploratory surgical approach for AD, and perianesthesia nursing care may support perioperative safety, recovery, and complication prevention in this context. Further controlled studies with longer follow-up are needed.},
}

@article {pmid42897209,
year = {2026},
author = {Santoro, JD and Abdel-Latif, S and Banerjee, AK and Mager, H and Silverman, M and Kazerooni, L and Otey, ST and Yousuf, MM and Lucas, MC and Schlachetzki, Z and Rissman, RA and Rafii, MS},
title = {Phosphorylated tau 217 in young adults with Down syndrome and Down syndrome regression disorder.},
journal = {Communications medicine},
volume = {6},
number = {1},
pages = {},
pmid = {42897209},
issn = {2730-664X},
support = {K23 HL155898/HL/NHLBI NIH HHS/United States ; K23HL155898//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; },
abstract = {BACKGROUND: Down syndrome regression disorder (DSRD) causes a rapid loss of cognitive, behavioral, and daily living skills, usually in adolescents and young adults with Down syndrome. Because people with Down syndrome have a high lifetime risk of Alzheimer's disease, we examined whether DSRD is associated with an Alzheimer-related pattern of tau pathology.

METHODS: In this prospective, single-center study, we measured plasma phosphorylated tau-217 (p-tau217), a blood marker of Alzheimer pathology, in 132 participants: 48 with DSRD, 39 with Down syndrome without regression (DSwR), and 45 neurodevelopmental controls. We compared p-tau217 concentrations across groups and examined relationships with demographic factors, medical conditions, treatment status, and diagnostic test abnormalities.

RESULTS: Median p-tau217 concentrations were similar in the DSRD (0.082 pg/mL), DSwR (0.084 pg/mL), and neurodevelopmental control (0.080 pg/mL) groups (overall comparison, p  =  0.57). Pairwise comparisons and models accounting for demographic and clinical factors also showed no statistically significant group differences. Among participants with DSRD, p-tau217 was not associated with treatment status or abnormalities on brain-wave testing, neuroimaging, or cerebrospinal fluid analysis. No clinical or demographic factor remained associated with p-tau217 after accounting for the number of analyses performed.

CONCLUSIONS: These findings provide no evidence of a group-level Alzheimer-related p-tau217 elevation in young people with DSRD and support DSRD as a condition distinct from Alzheimer's disease. However, a single blood measurement cannot exclude Alzheimer pathology in an individual. Longitudinal studies using several complementary biomarkers are needed.},
}

@article {pmid42897323,
year = {2026},
author = {Armbrust, F and Bruhn, H and Bickenbach, K and Steen, N and Shcoory, S and Afratis, N and Korn, N and Körschgen, H and Moali, C and Pietrzik, CU and Sagi, I and Becker-Pauly, C},
title = {Meprin β is specifically inhibited by its cognate synthetic propeptide.},
journal = {Cellular and molecular life sciences : CMLS},
volume = {83},
number = {1},
pages = {},
pmid = {42897323},
issn = {1420-9071},
mesh = {*Metalloendopeptidases/antagonists & inhibitors/metabolism ; Humans ; Animals ; *Protease Inhibitors/pharmacology/chemistry ; *Peptides/pharmacology/chemistry/chemical synthesis ; Mice ; Hydroxamic Acids/pharmacology ; },
abstract = {Meprin β is a zinc-dependent metalloprotease of the astacin family highly expressed in kidney and intestine. Dysregulation of meprin β expression and activity was observed in several pathological conditions such as Alzheimer's disease, cancer, fibrosis, and inflammatory bowel disease. Therefore, inhibition of meprin β could be a promising therapeutic option to treat pathological conditions influenced by this protease. However, available small-molecule compounds such as the broad-spectrum metalloproteinases inhibitors marimastat or actinonin lack specificity. Hence, more selective meprin β inhibitors needs to be developed. Here, we provide evidence that the synthetically generated cognate meprin β propeptide serves as highly specific inhibitor for the protease (IC50 = 1.35 µM), while other related metalloproteases such as meprin α and a disintegrin and metalloproteinases (ADAMs) are not affected. Employing a targeted approach revealed that removal of the last four C-terminal amino acids of the propeptide significantly improved its inhibitory capacity (IC50 = 0.68 µM). In cell-based experiments, treatment with the propeptide resulted in diminished meprin β activity and decreased cleavage of its substrates, including the interleukin-6 receptor (IL-6R) and the G protein-coupled receptor latrophilin-3 (LPHN3). Suitability was further confirmed in ex vivo cultivated organotypic brain slices, where the administration of the propeptide also resulted in decreased meprin β activity and diminished latrophilin-3 cleavage. Thus, not only the synthetic wildtype propeptide but especially a C-terminally truncated propeptide of meprin β represent highly specific inhibitors with potential for therapeutic application.},
}

*Metalloendopeptidases/antagonists & inhibitors/metabolism
Humans
Animals
*Protease Inhibitors/pharmacology/chemistry
*Peptides/pharmacology/chemistry/chemical synthesis
Mice
Hydroxamic Acids/pharmacology

@article {pmid42897722,
year = {2026},
author = {Grewal, P and Seidman, MB and Chasen, J and Lench, D and Dickens, I and Brennan, EA and Rodriguez-Porcel, F and Kindred, J and George, MS and Kautz, S and Caulfield, KA and McTeague, LM},
title = {Brain Stimulation as a Treatment for Apathy: A Scoping Review of Effects and Safety.},
journal = {The Journal of neuropsychiatry and clinical neurosciences},
volume = {},
number = {},
pages = {appineuropsych20250297},
doi = {10.1176/appi.neuropsych.20250297},
pmid = {42897722},
issn = {1545-7222},
abstract = {OBJECTIVE: Apathy is a neuropsychiatric syndrome characterized by impairment of goal-directed behavior, cognition, and emotional responsiveness. In this scoping review, the authors evaluated the literature on brain stimulation for the treatment of patients with apathy across diagnostic categories and provide recommendations to guide future research and practice.

METHODS: The authors searched PubMed, Scopus, and PsycInfo for studies involving brain stimulation for apathy as a primary or secondary outcome.

RESULTS: From 1,209 records, 52 studies evaluating brain stimulation were included; of these, 10 systematic reviews or meta-analyses were synthesized separately. Modalities included repetitive transcranial magnetic stimulation (rTMS; N=26), deep brain stimulation (DBS; N=7), transcranial direct current stimulation (tDCS; N=6), electroconvulsive therapy (N=1), transcranial alternating current stimulation (N=1), and transcranial pulsating electromagnetic field therapy (N=1). Populations included patients with schizophrenia (N=477), Parkinson's disease (PD; N=289), depression (N=288), Alzheimer's disease (AD) and mild cognitive impairment (MCI) (N=210), Huntington's disease (N=42), PD with MCI (N=28), traumatic brain injury (N=28), stroke (N=14), COVID-19 (N=12), and dementia with Lewy bodies (N=6) (total N=1,366). rTMS improved apathy measures, most consistently in AD, with positive trends in depression, MCI, stroke, and schizophrenia. tDCS showed variable effects, with some benefits for schizophrenia. DBS showed mixed results, varying with stimulation location. Observed adverse events were mild and modality specific.

CONCLUSIONS: Investigations into brain stimulation as a treatment for apathy show some promise. Conclusions were limited by small sample sizes, heterogeneous study designs, and variable outcome measures. Randomized trials with common validated apathy instruments, standardized stimulation parameters, and harmonized diagnostic measures may help advance the field.},
}

@article {pmid42897836,
year = {2026},
author = {Kumari, P and Sathyanarayanan, A and Pimpalkar, K and Kumar, A and Kumar, D and Chopade, S},
title = {Design, In Silico Targeting, and Characterization of Curcumin-Ibuprofen Prodrug Microspheres for Brain-Specific Delivery in Alzheimer's Therapy.},
journal = {Current pharmaceutical design},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113816128447768260915075822},
pmid = {42897836},
issn = {1873-4286},
abstract = {INTRODUCTION: Alzheimer's Disease (AD) is a complex neurodegenerative condition characterized by limited treatment effectiveness, attributed to inadequate Blood-Brain Barrier (BBB) permeability and low medication absorption. Curcumin and ibuprofen possess anti-inflammatory and neuroprotective properties but are limited by pharmacokinetic constraints. This study aimed to synthesize a curcumin-ibuprofen mutual prodrug (CIP), formulate it into chitosan-based microspheres (CIPM), and evaluate its neuroprotective potential for brain-targeted delivery in AD.

METHODS: CIP was synthesized via ethylenediamine carbodiimide (EDCI) mediated esterification and confirmed through IR, NMR, LC-MS, and DSC. CIPM microspheres were prepared using emulsion crosslinking, characterized by scanning electron microscopy, drug entrapment efficiency (85.5%), zeta potential, particle size analysis, and DSC. In silico tools (SwissADME, ProTox-II) and molecular docking were used to assess ADMET profiles and target binding (AChE, BACE1, β-secretase). Network pharmacology identified overlapping targets between curcumin and AD. In vivo evaluation was conducted in a TMT (Trimethyltin)- induced neurodegeneration rat model through behavioral Morris Water Maze (MWM), Novel Object Recognition (NOR), Social Recognition Test (SRT), and biochemical and histological assessments.

RESULTS: CIP demonstrated strong binding affinity with AD-related targets (-10.0 to -8.5 kcal/mol) and favorable ADMET properties. Network analysis identified 226 overlapping targets and key hub genes. CIPM significantly improved cognitive performance, antioxidant enzyme levels, and neuronal integrity compared to individual drugs and showed comparable efficacy to donepezil.

DISCUSSION: The present study demonstrates that the curcumin-ibuprofen conjugate, when delivered through chitosan-based microspheres, effectively enhances brain targeting and overcomes pharmacokinetic barriers. The formulation not only improved drug bioavailability but also showed superior neuroprotective and cognitive benefits compared to individual drugs. Molecular docking and network pharmacology further confirmed its multi-target potential, suggesting a synergistic mechanism in modulating key AD pathways. These outcomes highlight CIPM as a promising candidate that warrants further pharmacokinetic and clinical validations for Alzheimer's therapy.

CONCLUSION: The curcumin-ibuprofen prodrug-loaded microspheres present a promising brain-targeted treatment approach for Alzheimer's disease by improving bioavailability, engaging multiple targets, and providing neuroprotection.},
}

@article {pmid42898005,
year = {2026},
author = {Rosenberg, A and Rennie, A and Ekman, U and Daniilidou, M and Hall, A and Matton, A and Solomon, A and Wahlund, LO and Kivipelto, M and Westman, E},
title = {Real-World Patient Eligibility for Alzheimer's Disease Anti-Amyloid Therapy in Seven Swedish Memory Clinics.},
journal = {European journal of neurology},
volume = {33},
number = {10},
pages = {e70786},
pmid = {42898005},
issn = {1468-1331},
support = {101112145//Innovative Health Initiative/ ; 101132933//Innovative Health Initiative/ ; //Region Stockholm (ALF)/ ; FoUI-104172//Center for Innovative Medicine/ ; 357810//EU Joint Programme - Neurodegenerative Disease Research/ ; AF-1031812//Alzheimerfonden/ ; 2025-02405//Vetenskapsrådet/ ; //Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse/ ; FO2026-0228//Hjärnfonden/ ; 2025-02071//Forskningsrådet om Hälsa, Arbetsliv och Välfärd/ ; 2025-03749//VINNOVA/ ; },
mesh = {Humans ; *Alzheimer Disease/drug therapy/cerebrospinal fluid ; Sweden ; Female ; Male ; Aged ; *Amyloid beta-Peptides/cerebrospinal fluid ; Aged, 80 and over ; *Cognitive Dysfunction/drug therapy/cerebrospinal fluid ; *Eligibility Determination ; Cohort Studies ; },
abstract = {BACKGROUND: Anti-amyloid therapies lecanemab and donanemab are the first potentially disease-modifying treatments for Alzheimer's disease (AD) approved in Europe. We estimated real-world eligibility for these treatments in a large multicenter memory clinic patient cohort in Sweden (MemClin).

METHODS: MemClin included patients with a first diagnostic visit between 2016 and 2022 at seven specialist memory clinics in Stockholm, Sweden. To estimate eligibility for anti-amyloid therapy, we applied key inclusion/exclusion criteria from the lecanemab and donanemab appropriate use recommendations. Eligible patients were required to have (1) a clinical diagnosis of AD-type dementia or mild cognitive impairment (MCI), (2) confirmed Aβ pathology (abnormal CSF Aβ42) and (3) no apparent medical exclusion criteria. Eligibility was calculated for different scenarios to provide both upper-bound estimates (main analysis) and more conservative, implementation-ready estimates of near-term treatable patients (sensitivity analysis).

RESULTS: Cohort consisted of 2126 patients (mean age 77.1 ± 6.6 years; 61.8% MCI, 24.2% dementia, 13.7% subjective cognitive impairment). In the main analysis, 11.5% of the whole cohort was estimated to be eligible for either treatment (lecanemab 10.6%, donanemab 11.5%). Most eligible patients had early-stage disease (61.9% MCI vs. 38.1% dementia) and an A + T- biomarker profile, that is, normal biomarker of tau (57.9%). Eligibility was markedly lower in sensitivity analyses (e.g., 2.7% when all patients without MRI were assumed ineligible).

CONCLUSIONS: Even upper-bound estimates indicate that a minority of real-world memory clinic patients may currently qualify for anti-amyloid therapy. These findings provide timely evidence to inform the ongoing debate on the implementation of anti-amyloid therapy in public healthcare.},
}

Humans
*Alzheimer Disease/drug therapy/cerebrospinal fluid
Sweden
Female
Male
Aged
*Amyloid beta-Peptides/cerebrospinal fluid
Aged, 80 and over
*Cognitive Dysfunction/drug therapy/cerebrospinal fluid
*Eligibility Determination
Cohort Studies

@article {pmid42898907,
year = {2026},
author = {Wicker, A and Courtright-Lim, A and Tilburt, J},
title = {Ethical challenges in the clinical translation of anti-amyloid monoclonal antibodies for Alzheimer's disease: a scoping review.},
journal = {Frontiers in psychiatry},
volume = {17},
number = {},
pages = {1953954},
pmid = {42898907},
issn = {1664-0640},
abstract = {BACKGROUND: The development and evaluation of anti-amyloid beta monoclonal antibodies (mAbs) for the treatment of Alzheimer's disease have been accompanied by extensive ethical debate spanning clinical trials, regulatory processes, prescribing practices, and healthcare delivery. This scoping review examined literature published between 2006 and 2026 to identify and clarify the landscape of ethical considerations surrounding the implementation, prescribing, and delivery of anti-amyloid mAbs across both research and clinical settings.

METHODS: We searched PubMed, Scopus, Web of Science, Embase, and Ovid EBM Reviews (including CENTRAL and CDSR) from 2006 to March 2026 using a structured search strategy. Eligible publications focused on ethical issues associated with the clinical translation of anti-amyloid mAbs. Two reviewers independently screened titles, abstracts, and full-text articles, with duplicate extraction performed on an initial subset of publications. The review was conducted using JBI guidance and reported according to PRISMA-ScR.

RESULTS: We identified 84 publications from 23 countries published between 2014 and 2026, including 12 original research studies, 1 systematic review, and 71 commentaries, narrative reviews, legal analyses, or practice guidelines. Analysis identified 32 subthemes, which were synthesized into 7 overarching themes: (1) beneficence and nonmaleficence, (2) respect for persons, (3) equity and accessibility, (4) evidence and trial integrity, (5) governance and stewardship, (6) relational and social impacts, and (7) health system readiness and sustainability. Among the 32 subthemes, uncertain clinical benefit and risk of harm (both within the beneficence and nonmaleficence theme) were discussed most frequently within the literature, each appearing in 61 publications.

CONCLUSIONS: The biomedical literature documents a broad range of ethical considerations relating to anti-amyloid mAbs. Despite this growing literature, it is primarily based on commentary, with few empirical studies, and even fewer incorporating the perspectives of patients, families, and clinicians. Doing so may add further context and nuance to ethical discussion about mAbs in the years ahead.},
}

@article {pmid42899916,
year = {2026},
author = {Vasenina, EE},
title = {[Mild cognitive impairment as a heterogeneous condition: From diagnostic algorithm - to individualized therapeutic approaches].},
journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova},
volume = {126},
number = {9},
pages = {42-51},
doi = {10.17116/jnevro202612609142},
pmid = {42899916},
issn = {1997-7298},
mesh = {Humans ; *Cognitive Dysfunction/diagnosis/drug therapy/etiology/therapy/epidemiology ; Disease Progression ; Algorithms ; Neuropsychological Tests ; Risk Factors ; Precision Medicine ; Dementia/etiology/prevention & control ; },
abstract = {Mild cognitive impairment (MCI) is a prevalent syndrome affecting approximately 10-15% of the global population. In the Russian Federation, the estimated number of individuals with MCI may reach 5 million, with continued growth projected. Subjective cognitive deficits are linked to an increased risk of dementia, although memory complaints are often regarded as a normal aspect of aging. Standard neuropsychological assessments, including the Mini-Mental State Examination (MMSE), Mini-Cog, and Montreal Cognitive Assessment (MoCA), often lack sufficient sensitivity to detect MCI, particularly in individuals with high cognitive reserve. MCI has multiple etiologies, including depression and other affective disorders, severe somatic diseases, traumatic or toxic brain injury, and neurodegenerative or vascular pathologies of the central nervous system. This etiological diversity leads to variable clinical outcomes: cognitive function may return to age-appropriate norms in some instances, while in others, early impairment progresses to dementia. High-risk factors for conversion from MCI to dementia include the amnestic subtype of cognitive impairment, slow gait, coexisting affective disorders, sensory deficits, senile preasthenia and asthenia, and sleep disturbances. Accurate prediction of disease progression is critical for informing therapeutic strategies. For patients at elevated risk of progression, pharmacological interventions should be selected not only for symptomatic management but also for their potential to delay conversion. In Russia, Miladean, a combination of memantine and melatonin, is approved for use in patients with MCI. In addition to its symptomatic benefits, Miladean exhibits neuroprotective and endothelioprotective properties, supporting its use as the preferred treatment for patients at high risk of MCI progression.},
}

Humans
*Cognitive Dysfunction/diagnosis/drug therapy/etiology/therapy/epidemiology
Disease Progression
Algorithms
Neuropsychological Tests
Risk Factors
Precision Medicine
Dementia/etiology/prevention & control

@article {pmid42900219,
year = {2026},
author = {Giri, N and Chakraborty, A},
title = {Nanomaterial Design for Macrophage Reprogramming: Emerging Strategies and Mechanistic Insights for Inflammation and Tumor Therapy.},
journal = {ACS applied bio materials},
volume = {},
number = {},
pages = {},
doi = {10.1021/acsabm.6c01937},
pmid = {42900219},
issn = {2576-6422},
abstract = {Macrophages play a paradoxical role in inflammation and tumor. They can protect the host during acute inflammation but act as the main driver for the chronic inflammation which is a common characteristic of several diseases including rheumatoid arthritis, atherosclerosis, type 2 diabetes, inflammatory bowel disease, and neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. In the tumor microenvironment, macrophages switch their phenotype to the immunosuppressive M2 state that promotes tumor growth, angiogenesis, and metastasis. Emerging nanomaterial platforms are trying to offer transformative solutions by enabling the precise delivery of immunomodulatory drugs directly to disease-site macrophages. This review will provide comprehensive comparative analysis of these emerging nanomaterial designs strategies across two disease paradigms: inflammatory diseases and tumor. The discussion will focus on various strategies which include inhibiting chemokine axis (CCL2-CCR2 axis), selective elimination of macrophages through apoptosis, metabolic reprogramming, biomimetic and apoptotic cell-inspired nanoparticles leveraging natural macrophage clearance pathways to promote M2 polarization in inflammation, and the activation of tumor-associated macrophages via TLR and STING agonist. We highlight the role of nanoparticle surface chemistry, composition, and targeting ligands in achieving the two opposite therapeutic outcomes of these two diseases while maintaining some common design principles including EPR-mediated accumulation at the disease sites and biomimetic modifications. We also mentioned novel next-generation nanoparticle-based platforms that are currently in clinical trials for the treatment of tumor and inflammatory diseases. Finally, we discuss the barriers that limit the clinical translational potential of broad nanoparticles, with particular emphasis on nanoparticle-related immunotoxicity, macrophage heterogeneity, and manufacturing reproducibility of the nanoparticles.},
}

@article {pmid42900250,
year = {2026},
author = {Páez, A and Piñol-Ripoll, G and Dakterzada, F and Dang-Vu, TT},
title = {Sleep Spindles and Slow Oscillations as Potential Biomarkers and Therapeutic Targets in Mild-to-Moderate Alzheimer's Disease.},
journal = {Current neurology and neuroscience reports},
volume = {26},
number = {1},
pages = {},
pmid = {42900250},
issn = {1534-6293},
mesh = {Humans ; *Alzheimer Disease/physiopathology/therapy/diagnosis ; Biomarkers ; *Sleep/physiology ; Animals ; },
abstract = {PURPOSE OF REVIEW: This review critically evaluates evidence on sleep spindles (SP), slow oscillations (SOs), and their coordination in mild-to-moderate Alzheimer's disease (AD), focusing on their relationships with cognition, AD biomarkers, and their therapeutic potential.

RECENT FINDINGS: Longitudinal studies associate greater SP and/or SO activity with better cognition and favourable amyloid and tau profiles after clinical onset. Spindle and SO coupling may index network integrity. Preserved NREM sleep oscillations are associated with lower orexin concentrations and weaker adverse relationships between orexin and cognitive and neuropsychiatric outcomes. Closed-loop acoustic stimulation and slow-oscillatory transcranial direct-current stimulation can modify SO activity, spindle activity, and coupling, although cognitive and biomarker benefits remain uncertain. Spindle-SO activity, including their temporal coupling, are associated with cognition and AD biomarkers across the disease continuum. Closed-loop acoustic and electrical stimulation can modify these oscillations, but biomarker-characterized trials in MCI and AD are needed to determine whether treatment produces durable cognitive and biomarker benefits.},
}

Humans
*Alzheimer Disease/physiopathology/therapy/diagnosis
Biomarkers
*Sleep/physiology
Animals

@article {pmid42901167,
year = {2026},
author = {Perneczky, R and Schöll, M and Rauchmann, BS and Hofmann, A},
title = {More than just accuracy: A pathway-level framework for implementing blood and digital biomarkers for Alzheimer's disease care.},
journal = {Neuron},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuron.2026.09.006},
pmid = {42901167},
issn = {1097-4199},
abstract = {Blood biomarkers are transforming Alzheimer's disease diagnostics by enabling a scalable, minimally invasive assessment of pathology. Food and Drug Administration clearances and European market certifications of different plasma tests mark a shift toward biological diagnosis in routine care. However, clinical implementation is not guided by diagnostic accuracy alone but will depend on improved patient-centered and pathway-level outcomes, including diagnostic confidence, the appropriate use of CSF and PET assessments, time to diagnosis, amyloid-targeting treatment eligibility assessment, and trial recruitment. Digital biomarkers may complement blood tests by providing repeated measures of cognition, speech, and mobility. Yet, their evidence base remains more heterogeneous regarding construct validity, supervision requirements, device dependence, adherence burden, cultural portability, interpretability, and regulatory classification. This review defines how combined blood-digital workflows could be evaluated beyond accuracy, including the context of use, downstream decisions, ethical aspects, governance, and post-market monitoring, ultimately aiming to translate biomarker innovation into meaningful benefits for patients and health systems.},
}

@article {pmid42901789,
year = {2026},
author = {Maekawa, H},
title = {[Intravenous Thrombolysis for Acute Ischemic Stroke: Current Evidence and Perspectives].},
journal = {No shinkei geka. Neurological surgery},
volume = {54},
number = {5},
pages = {996-1004},
doi = {10.11477/mf.030126030540050996},
pmid = {42901789},
issn = {0301-2603},
mesh = {Humans ; Administration, Intravenous ; *Brain Ischemia/drug therapy ; Fibrinolytic Agents/administration & dosage/therapeutic use ; *Ischemic Stroke/drug therapy ; *Thrombolytic Therapy/methods ; Tissue Plasminogen Activator/therapeutic use/administration & dosage ; },
abstract = {Since its introduction, intravenous thrombolysis (IVT) with alteplase has remained a mainstay of reperfusion therapy in the hyperacute management of acute ischemic stroke (AIS). Recent clinical evidence has driven a major paradigm shift from a strictly "time-based" approach to a "tissue-based" approach. Advanced neuroimaging techniques, including diffusion-weighted imaging-fluid-attenuated inversion recovery (DWI-FLAIR mismatch) and perfusion mismatch analyses, have enabled extension of the treatment window beyond 4.5 h and treatment of patients with strokes of unknown onset, particularly benefiting those who are ineligible for endovascular thrombectomy (EVT). Furthermore, the treatment criteria have been refined to recommend IVT for disabling deficits regardless of the baseline stroke severity score while withholding it from patients with minor, nondisabling presentations. An emerging challenge in clinical practice is determining whether IVT should be contraindicated in patients receiving novel amyloid-targeting therapies for Alzheimer's disease. Meanwhile, prehospital protocols involving mobile stroke units (MSUs) may help reduce onset-to-needle time in selected regions. IVT continues to evolve through personalized patient selection aimed at maximizing safety and improving functional outcomes.},
}

Humans
Administration, Intravenous
*Brain Ischemia/drug therapy
Fibrinolytic Agents/administration & dosage/therapeutic use
*Ischemic Stroke/drug therapy
*Thrombolytic Therapy/methods
Tissue Plasminogen Activator/therapeutic use/administration & dosage

@article {pmid42885677,
year = {2026},
author = {Pandey, JP},
title = {Immunoglobulin GM (γ marker) allotypes as potential genetic markers of efficacy of lecanemab therapy in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261500140},
doi = {10.1177/13872877261500140},
pmid = {42885677},
issn = {1875-8908},
abstract = {Lecanemab is a humanized IgG1 monoclonal antibody that targets amyloid-β (Aβ) aggregates, a pathological hallmark of Alzheimer's disease (AD). In the largest clinical trial of its kind to date, lecanemab slowed cognitive decline by 27% in patients with early-stage AD. Lecanemab has also been shown to reduce cerebral Aβ deposition. Lecanemab expresses the immunoglobulin GM 3 allotype, which is defined by an arginine residue in the CH1 region of the γ1 chain and is potentially immunogenic in individuals who lack this allotype. I hypothesize that anti-GM 3 antibodies, generated either following lecanemab administration or acquired previously through maternal-fetal incompatibility or transfusion of allotype-incompatible blood products, may form immune complexes with the therapeutic antibody. These immune complexes could be cleared by phagocytic cells, including microglia, thereby reducing the availability and efficacy of lecanemab and contributing to therapeutic nonresponsiveness. If validated, GM allotypes could serve as genetic markers for predicting response to lecanemab therapy and may help guide personalized treatment strategies in AD.},
}

@article {pmid42885691,
year = {2026},
author = {Alavi, A and Høilund-Carlsen, PF},
title = {The critical role of PET-based assessment of cerebrovascular disease in the management of patients with cognitive impairment and dementias.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261497232},
doi = {10.1177/13872877261497232},
pmid = {42885691},
issn = {1875-8908},
abstract = {A recent survey provides valuable insights into French practitioners' preparedness for implementing anti-amyloid immunotherapy (AAI) for Alzheimer's disease. It highlights the need for education but also underscores a broader challenge: clinicians must understand not only treatment protocols but also unresolved issues regarding diagnostic specificity, efficacy, safety, and cost-effectiveness. Amyloid biomarkers should not be considered definitive indicators of disease causality or treatment response. Greater attention should also be given to functional imaging approaches and cerebrovascular pathology, which may contribute to a more comprehensive understanding of cognitive decline. A balanced, evidence-based approach is essential before widespread adoption of AAI.},
}

@article {pmid42885915,
year = {2026},
author = {Gries, M and Schäfer, KH and Endres, K},
title = {Targeting the microbiota-gut-brain axis in Alzheimer's and Parkinson´s disease: recent therapeutic approaches.},
journal = {Expert opinion on therapeutic targets},
volume = {},
number = {},
pages = {},
doi = {10.1080/14728222.2026.2748747},
pmid = {42885915},
issn = {1744-7631},
abstract = {INTRODUCTION: Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common neurodegenerative disorders with limited disease-modifying treatment options. Evidence suggests that the microbiota-gut-brain axis (MGBA) plays a role in these diseases by facilitating communication between the gut and the central nervous system. Associations have been found between altered gut microbiota composition and function, impaired barrier integrity, dysregulated metabolite production, and immune activation to neuroinflammation and progressive neurodegeneration.

AREAS COVERED: This review summarizes and critically assesses recent studies from the past year to provide an updated overview of therapeutic strategies targeting the MGBA in both diseases. We discuss dietary interventions, probiotics, postbiotics, microbial metabolites, and approaches targeting gut barrier function. We also highlight strategies such as fecal transplantation, photobiomodulation, and PD-targeted metabolism therapies using butyrate and resistant starch.

EXPERT OPINION: While these interventions have shown promising results in preclinical and early clinical trials, their clinical application is limited by methodological heterogeneity, interindividual variability and a lack of standardized protocols. Successful implementation requires carefully designed clinical trials, particularly longitudinal studies of presymptomatic cohorts, standardized microbiome analyses, and integrated multi-omics approaches to elucidate causal relations and facilitate personalized treatment strategies.},
}

@article {pmid42887669,
year = {2026},
author = {Otto, B and Zantvoord, JB and Siskind, D and Vermeulen, JM},
title = {Modulating neuroinflammation with glucagon-like peptide-1 receptor agonists: a scoping review exploring their therapeutic potential in schizophrenia.},
journal = {Progress in neuro-psychopharmacology & biological psychiatry},
volume = {},
number = {},
pages = {111978},
doi = {10.1016/j.pnpbp.2026.111978},
pmid = {42887669},
issn = {1878-4216},
abstract = {Neuroinflammation is a key contributor to the pathophysiology and symptomatology of schizophrenia spectrum disorders. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), clinically approved anti-diabetic and -obesity medication, have been associated with anti-inflammatory properties. It remains unclear whether GLP-1RA treatment can improve neuroinflammation within psychiatric disorders, including schizophrenia. This scoping review synthesizes evidence from clinical and preclinical studies on the anti-inflammatory effects of GLP-1RAs in psychiatric, neurodegenerative and neurological disease models, identifying crucial research gaps and providing future recommendations to guide potential clinical translation. The literature search was conducted in PubMed, Embase and PsycINFO and included outcomes of cytokine levels within blood and brain samples. Within the 40 included studies, two were clinical (schizophrenia and alcohol-use disorder) and 38 were preclinical models of psychiatric diseases, Alzheimer's -, Parkinson's Disease, Multiple Sclerosis, Epilepsy and lipopolysaccharide (LPS)-induced neuroinflammation. Preclinical studies showed anti-(neuro)inflammatory effects of GLP-1RAs, whereas the two available clinical studies found no significant changes in peripheral inflammatory markers. As these trials were not primarily designed or powered to test neuroinflammatory effects, the clinical findings remain inconclusive. Differences in study design, inflammatory measurements, pharmacokinetics and dosing may have contributed to the discrepancy between preclinical and clinical findings. Future research should prioritize early-phase dose-finding trials in non-diabetic, or -overweight patients diagnosed with schizophrenia spectrum disorders, evaluating the effects of alternative GLP-1RA regimens on neuroinflammatory markers, safety and clinical symptomatology. This is an essential step to determine their potential mental health-enhancing effects through the modulation of neuroinflammation within schizophrenia spectrum disorders.},
}

@article {pmid42887705,
year = {2026},
author = {Roy, J and Tsui, KC and Poon, CH and Zhang, J and Lai, Y and Wong, KY and Mihardja, M and Tse, V and Li, PC and Au, C and Ng, J and Kocabicak, E and Aquili, L and Wong, KH and Lu, Z and Temel, Y and Fung, ML and Lim, LW},
title = {Melatonin ameliorates behavioral deficits in 5xFAD mice through modulation of neurogenesis, neuroimmune responses, neurotransmission, and metabolic pathways.},
journal = {Brain, behavior, and immunity},
volume = {},
number = {},
pages = {107077},
doi = {10.1016/j.bbi.2026.107077},
pmid = {42887705},
issn = {1090-2139},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder with limited disease-modifying treatment options. Melatonin, an endogenous hormone, has been shown to have therapeutic effects on amyloid deposition, oxidative stress, and neuroinflammation in AD. However, the mechanisms of its neuroprotective effects in the hippocampus remain largely unknown. This study aimed to investigate the multi-mechanistic neuroprotective effects of melatonin in AD. Eight-month-old female 5xFAD transgenic mice were treated with melatonin (10 mg/kg) for 4 weeks. Temozolomide and bromodeoxyuridine were used to block neurogenesis and to label proliferating neurons, respectively. Our results showed that 5xFAD mice treated with melatonin exhibited improved exploratory behavior, enhanced memory performance, reduced depressive-like symptoms, and decreased levels of stress hormones. At the molecular level, melatonin reduced amyloid-beta (Aβ) plaque accumulation, elevated hippocampal neurogenesis markers (DCX and BrdU), increased Trem2 expression and anti-inflammatory microglial activation, restored serotonergic, dopaminergic, catecholaminergic, and GABAergic neurotransmission, and partially normalized broader hippocampal metabolic pathways. Notably, temozolomide treatment abrogated the beneficial effects of melatonin on memory performance and depressive-like behavior in 5xFAD mice, indicating a neurogenesis-dependent mechanism. Collectively, these findings suggest that melatonin ameliorates behavioral deficits in 5xFAD mice through both neurogenesis-independent (reduced Aβ plaque accumulation, Trem2-microglial activation, neurotransmission restoration, and metabolic remodeling) and hippocampal neurogenesis-dependent mechanisms. Overall, melatonin holds therapeutic potential for attenuating the neuropathology and behavioral deficits in AD.},
}

@article {pmid42888370,
year = {2026},
author = {Porsteinsson, AP and Chumki, SR and Palma, AM and Zhang, Z and Wang, D and Such, P and Montano, CB},
title = {Brexpiprazole for Individual Agitation Symptoms in Alzheimer's Dementia: A Caregiver-Centered Post Hoc Analysis.},
journal = {Neurology and therapy},
volume = {},
number = {},
pages = {},
pmid = {42888370},
issn = {2193-8253},
abstract = {INTRODUCTION: People with Alzheimer's dementia commonly experience agitation symptoms, which are distressing to caregivers and can influence long-term care decisions. The aim of this exploratory post hoc analysis was to test the hypothesis that brexpiprazole can improve individual agitation symptoms over 12 and 24 weeks, including symptoms that caregivers find the most distressing.

METHODS: Data were included from two phase 3, 12-week, randomized (brexpiprazole or placebo), double-blind trials and a phase 3, 12-week, brexpiprazole-treatment extension trial. Participants had Alzheimer's dementia with agitation, and lived at home or in long-term care. The frequency of 29 agitation symptoms over 12 and 24 weeks was assessed using Cohen-Mansfield Agitation Inventory (CMAI) item scores. The focus of this post hoc analysis was the 11 CMAI agitation symptoms that caregivers found the most distressing in a prior survey.

RESULTS: Among 610 participants (median age 74 years, 55.5% female, 44.5% male), each of the 11 most-distressing agitation symptoms reduced in frequency from baseline to Week 12, with further improvements to Week 24 (n = 159). Improvements over 12 weeks were numerically greater with brexpiprazole 2 or 3 mg/day (n = 363) compared with placebo (n = 247) on 9 of 11 symptoms: cursing or verbal aggression, spitting, repetitive sentences or questions, hitting, constant unwarranted requests for attention/help, trying to get to a different place, pacing or aimless wandering, grabbing onto people or things, and kicking. Each of the 18 other agitation symptoms (beyond the most distressing) also reduced in frequency. After 24 weeks, 15 of 29 agitation symptoms occurred less than once a week.

CONCLUSION: Brexpiprazole was associated with improvement in a range of agitation symptoms in people with Alzheimer's dementia, including those that are the most distressing to caregivers. These exploratory results suggest that brexpiprazole may improve the specific agitation symptoms that can have the biggest impact on the caregiver experience.

TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT01862640, NCT03548584, NCT03594123.},
}

@article {pmid42889642,
year = {2026},
author = {Wenhua, Y and Wenjing, M and Yan, D and Fei, L and Juan, C and Xia, T and Yu, G and Xin, L and Yanlin, H and Ya, G and Xuelin, Y and Jing, L and Meimin, J and Wenyi, L and Yilin, K and Hongke, L and Yating, L},
title = {Should ApoE4 gene editing therapy be approached with caution when AD is accompanied by retinal neurodegenerative diseases?.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1934307},
pmid = {42889642},
issn = {1664-2295},
mesh = {Humans ; *Apolipoprotein E4/genetics ; *Gene Editing/methods ; *Alzheimer Disease/genetics/therapy/complications ; *Genetic Therapy/methods ; Animals ; *Neurodegenerative Diseases/genetics/therapy/complications ; *Retinal Diseases/genetics/therapy/complications ; Macular Degeneration/genetics/therapy ; },
abstract = {Apolipoprotein E4 (ApoE4) is the strongest genetic risk factor for Alzheimer's disease (AD), and ApoE4-directed gene editing and gene therapy have emerged as promising therapeutic strategies for AD, although they remain investigational and are not yet an established mainstream treatment. Interestingly, however, ApoE4 is reported to be associated with a reduced risk of retinal degenerative diseases such as glaucoma, age-related macular degeneration (AMD), and diabetic retinopathy (DR). Therefore, should ApoE4 gene editing therapy be approached with caution when AD occurs concurrently with glaucoma, AMD, or DR? In view of these and based on the existing literature, the present study detailed the distinct roles of ApoE4 in AD, glaucoma, AMD, and DR, with a purpose to offer valuable insights into subsequent ApoE4 gene editing therapies. We also summarise the ApoE-targeted therapeutic programmes currently in preclinical and early clinical development, delineate the remaining translational challenges, and discuss how patients with coexisting retinal neurodegenerative disease might be evaluated and monitored.},
}

Humans
*Apolipoprotein E4/genetics
*Gene Editing/methods
*Alzheimer Disease/genetics/therapy/complications
*Genetic Therapy/methods
Animals
*Neurodegenerative Diseases/genetics/therapy/complications
*Retinal Diseases/genetics/therapy/complications
Macular Degeneration/genetics/therapy

@article {pmid42890205,
year = {2026},
author = {Ji, H and Yang, Y and Wu, X and Bao, E},
title = {Safety of lecanemab in real-world patients with Alzheimer's disease: a prospective, observational case series supported by FAERS signal analysis.},
journal = {Frontiers in neuroinformatics},
volume = {20},
number = {},
pages = {1977226},
pmid = {42890205},
issn = {1662-5196},
abstract = {OBJECTIVE: Lecanemab, a humanized immunoglobulin monoclonal antibody, has been approved for the treatment of Alzheimer's disease (AD). Although clinical trials have demonstrated its favorable safety profile, real-world studies are crucial for identifying rare adverse events (AEs) and evaluating post-marketing safety. This study aimed to evaluate the safety of lecanemab by combining a clinical prospective, observational case cohort with data from the FAERS database, thereby providing a robust basis for the identification of potential safety signals.

METHODS: A prospective and observational study was conducted on patients with mild-to-moderate AD receiving lecanemab treatment at a tertiary medical center in China from July 2024 to February 2026. Extracted data included demographic characteristics, time to onset of AEs, and clinical symptoms. Exposure-adjusted incidence rates were calculated per 100 patient-years (PYs). Disproportionality analysis was performed using the US Food and Drug Administration Adverse Event Reporting System (FAERS), and safety signals for AEs observed in the cohort were evaluated utilizing reporting odds ratios (RORs) and proportional reporting ratios (PRRs). Additionally, data from these two real-world sources were compared and cross-validated.

RESULTS: The single-center prospective study enrolled a total of 91 patients. The median duration of lecanemab treatment was 185 days. Thirteen AEs were recorded (56.48/100 PYs), with the most frequent being amyloid-related imaging abnormalities-hemosiderin deposition (ARIA-H; defined as microhemorrhages and hemosiderin deposition) (12.39/100 PYs) and infusion-related reactions (IRRs) (8.85/100 PYs). In the FAERS database, the most frequently reported preferred terms (PTs) included headache, amyloid-related imaging abnormalities-edema/effusion (ARIA-E), ARIA-H, and IRRs. The majority of AEs occurred within the first 1-2 months after initiating lecanemab treatment (n = 393, 45.65%). Furthermore, FAERS analysis revealed a potential safety signal for cerebral infarction. However, this finding must be interpreted cautiously due to the lack of complete data on traditional stroke risk factors and concomitant antithrombotic use in spontaneous reports.

CONCLUSION: In this single-center prospective observational study, lecanemab demonstrated a generally favorable safety profile. Patients with AD aged 65 to 85 years represent a high-risk demographic for AEs. Particular clinical vigilance is required regarding the occurrence of AEs within the first two months of lecanemab initiation. Notably, ARIA (including both ARIA-E and ARIA-H) can occur at any phase during the treatment course.},
}

@article {pmid42890315,
year = {2026},
author = {Cutler, J and Tran, BA and Bullers, K and Fox, C},
title = {Lecanemab-Monoclonal Antibodies for the Treatment of Early Alzheimer's Disease.},
journal = {The Journal of pharmacy technology : jPT : official publication of the Association of Pharmacy Technicians},
volume = {},
number = {},
pages = {87551225261492568},
pmid = {42890315},
issn = {8755-1225},
abstract = {OBJECTIVE: Review the pharmacology, efficacy, and safety of lecanemab, a humanized immunoglobulin gamma 1 (IgG1) monoclonal antibody, for the treatment of early Alzheimer's disease (AD).

DATA SOURCES: Comprehensive search of Embase, PubMed, International Pharmaceutical Abstracts, Cochrane CENTRAL, Scopus, Web of Science, and Google Scholar were conducted from inception through December 2025.

Phase I-III clinical trials, systematic reviews, and meta-analyses evaluating lecanemab pharmacology, pharmacokinetics, efficacy, and safety were included. Product labeling was reviewed to supplement clinical data.

DATA SYNTHESIS: In the phase III Clarity AD trial, patients were randomized 1:1 to lecanemab 10 mg/kg every 2 weeks or placebo. The primary endpoint was change from baseline in Clinical Dementia Rating Sum of Boxes (CDR-SB) score at 18 months. Lecanemab demonstrated a mean change of 1.21 versus 1.66 with placebo (difference, -0.45; 95% CI, -0.67 to -0.23; P < .001). Secondary endpoint, amyloid burden via positron emission tomography (PET) scans (n = 698) showed -55.48 centiloids with lecanemab versus 3.64 with placebo (difference -59.12 centiloids; 95% CI, -62.64 to -55.6; P < .001). Additional endpoints included changes in ADAS-cog 14, ADCOMS, and ADCS-MCI-ADL scores favoring lecanemab over placebo. Lecanemab was well tolerated; infusion site reactions occurred in 26.4%. Amyloid-related imaging abnormalities (ARIA-E) occurred in 12.6% of participants.

CONCLUSION: Compared to placebo, lecanemab demonstrated statistically significant slowing of cognitive decline on CDR-SB and secondary endpoints, including amyloid burden reduction. However, its clinical benefit must be weighed against ARIA risk and substantial financial burden. Current evidence supports its use in carefully selected patients with early AD under close supervision.},
}

@article {pmid42890532,
year = {2026},
author = {Xi, Q and Wang, S and Shi, Q and Wang, H and Sun, P and Jin, Y and Ma, Y},
title = {Emerging roles of plant-derived extracellular vesicles in the management of dental diseases.},
journal = {Extracellular vesicles and circulating nucleic acids},
volume = {7},
number = {3},
pages = {1600-1624},
pmid = {42890532},
issn = {2767-6641},
abstract = {Dental diseases, including dental caries, pulpitis, and periodontitis, can cause pain and tooth loss, compromising mastication, speech, aesthetics, and quality of life. These diseases have also been associated with systemic disorders, including Alzheimer's disease. Conventional interventions, such as restorative procedures, root canal treatment, and periodontal scaling, have inherent limitations, underscoring the clinical need for novel therapeutic strategies. Plant-derived extracellular vesicles (PDEVs) have recently attracted considerable attention owing to their wide availability, cost-effectiveness, favourable biosafety profile, and capacity to mediate cross-kingdom communication. PDEVs exert diverse biological effects, including antimicrobial, anti-inflammatory, immunomodulatory, and tissue-regenerative activities. For example, ginger-derived PDEVs suppress the growth and virulence of Porphyromonas gingivalis through their lipid and miRNA cargoes, thereby alleviating periodontitis in mice. Given that effective dental therapy requires antimicrobial action, anti-inflammatory effects, immunomodulation, and tissue regeneration, PDEVs are promising therapeutic modalities. This review summarises the isolation, characterisation, composition, and biological functions of PDEVs, and discusses their potential applications in the management of dental diseases.},
}

@article {pmid42891424,
year = {2026},
author = {Tampi, RR and Murphy, K and Golden, J and Schuster, H and Conyers, R},
title = {A review of dextromethorphan and bupropion (Auvelity™) for the treatment of agitation in Alzheimer's disease.},
journal = {Drugs in context},
volume = {15},
number = {},
pages = {},
pmid = {42891424},
issn = {1745-1981},
abstract = {Dextromethorphan hydrobromide and bupropion hydrochloride extended-release tablets (Auvelity[TM]) became the second medication to be approved by the FDA for the treatment of agitation in Alzheimer's disease dementia after brexpiprazole. It also became the first non-antipsychotic medication to be approved for this specific indication. In this Editorial, the available data regarding the efficacy and adverse effects of this medication in the treatment of agitation in Alzheimer's disease dementia are reviewed.},
}

@article {pmid42884579,
year = {2026},
author = {Intharuksa, A and Prasansuklab, A and Techarang, T and Chaikhong, K and Arunotayanun, W and Jenraumjit, R},
title = {The Role of Herbal Medicines in Cognitive Impairment: A Narrative Review of Neuroprotective Mechanisms and Therapeutic Perspectives.},
journal = {Nutrients},
volume = {18},
number = {19},
pages = {},
pmid = {42884579},
issn = {2072-6643},
mesh = {Humans ; *Neuroprotective Agents/therapeutic use/pharmacology ; Animals ; *Cognitive Dysfunction/drug therapy ; *Phytotherapy/methods ; *Plant Preparations/therapeutic use/pharmacology ; Plant Extracts/pharmacology/therapeutic use ; Plants, Medicinal ; Cognition/drug effects ; },
abstract = {Cognitive impairment encompasses a clinical spectrum ranging from mild cognitive impairment to dementia, particularly Alzheimer's disease (AD), and involves interconnected pathological processes including cholinergic dysfunction, oxidative stress, neuroinflammation, mitochondrial impairment, amyloid-β accumulation, tau hyperphosphorylation, and synaptic loss. Herbal medicines have attracted increasing attention because their complex phytochemical composition may provide multi-target neuroprotective effects. This narrative review aimed to summarize current preclinical and clinical evidence on herbal medicines and traditional herbal formulations for cognitive impairment, with emphasis on their mechanisms, therapeutic potential, safety, and translational limitations. Relevant evidence from in vitro studies, animal models, randomized clinical trials, systematic reviews, and meta-analyses was narratively synthesized. The review considered single herbal medicines, standardized extracts, isolated phytochemicals, and traditional multi-herbal formulations, together with their reported cognitive outcomes and molecular targets. Preclinical studies suggest that selected herbal preparations may modulate pathways implicated in cognitive impairment through acetylcholinesterase and butyrylcholinesterase inhibition, antioxidant and mitochondrial protection, suppression of neuroinflammatory signaling, modulation of amyloidogenic and tau-related pathways, and enhancement of BDNF/TrkB- and CREB-associated neuroplasticit; however, clinical evidence remains limited and heterogeneous. Clinical studies of Bacopa monnieri, Panax ginseng, Crocus sativus, and several traditional Chinese, Korean, and Persian formulations have reported improvements in memory and global cognitive measures, including MMSE, MoCA, and ADAS-cog scores. However, evidence remains constrained by heterogeneity of products, small sample sizes, short treatment periods, inconsistent outcome measures, limited biomarker integration, and incomplete long-term safety assessment. Herbal medicines show potential as preventive, complementary, or adjunctive approaches for cognitive impairment, but they cannot yet be considered established replacements for conventional therapy. Standardized products, rigorous pharmacokinetic and toxicological evaluation, disease-relevant models, and adequately powered multicenter trials are required to support evidence-based clinical application.},
}

Humans
*Neuroprotective Agents/therapeutic use/pharmacology
Animals
*Cognitive Dysfunction/drug therapy
*Phytotherapy/methods
*Plant Preparations/therapeutic use/pharmacology
Plant Extracts/pharmacology/therapeutic use
Plants, Medicinal
Cognition/drug effects

@article {pmid42884722,
year = {2026},
author = {Dube, K and Stoinescu, A and Sadler, J and Truong, M and Malakoti-Negad, N and Chaudhry, M and Talukdar, R and Cohen, J and Pandey, S},
title = {Multidimensional Neuroprotective Effects of Combined Ubisol-Q10 and Ashwagandha (Withania somnifera) in Male and Female 5XFAD Mice.},
journal = {Nutrients},
volume = {18},
number = {19},
pages = {},
pmid = {42884722},
issn = {2072-6643},
support = {809194//This work was supported through donations from the Szecsei and Dhar families (grant # 809194)./ ; },
mesh = {Animals ; Male ; Female ; *Neuroprotective Agents/pharmacology ; *Withania/chemistry ; *Alzheimer Disease/drug therapy/pathology ; *Plant Extracts/pharmacology ; Mice ; Disease Models, Animal ; Autophagy/drug effects ; Mice, Transgenic ; Brain/drug effects/pathology ; },
abstract = {BACKGROUND/OBJECTIVES: Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by interconnected pathological processes including mitochondrial dysfunction, oxidative stress, impaired autophagic processes, neuroinflammation, neuronal degeneration, and progressive functional decline. Natural health products (NHPs), coenzyme-Q10 (CoQ10) and Ashwagandha (Withania somnifera) (ASH), have been previously reported to possess antioxidant, anti-inflammatory, mitochondrial-supportive, neuroprotective, and neurotrophic properties. This work investigates the neuroprotective effects of a bioavailability-enhanced formulation, Ubisol-Q10 (UQ), and ethanolic ASH extract, combined as a "Tonic," across multiple domains of AD pathology.

METHODS: The effects of long-term administration were evaluated in male and female 5XFAD mice from 2.5 to 11 months of age. Longitudinal magnetic resonance imaging assessed hippocampal and white matter volumes, a frailty index assessed physiological resilience, Novel Object and Novel Location Recognition testing assessed spatial and non-spatial memory, while post-mortem Nissl, Golgi-Cox, and immunofluorescence evaluated cellular density, dendritic morphology, amyloid pathology, neuroinflammation, autophagy-associated signaling, and astrocytic activity.

RESULTS: Across these measures, Tonic treatment preserved brain volumes, reduced amyloid pathology and inflammation, and modulated autophagy-associated pathways. Treatment also preserved dendritic architecture, frailty progression, and novelty-recognition behavior. Females demonstrated particularly pronounced preservation of white matter structure and increased dendritic density, whereas males showed strong modulation of inflammatory and autophagy-associated markers. Astrocytic immunoreactivity also demonstrated sex- and region-specific patterns, suggesting that glial responses may contribute differently to structural preservation in males and females.

CONCLUSIONS: Together, these findings support that UQ + ASH may provide diverse protection against AD neurodegeneration. The observed sex-specific responses emphasize the importance of incorporating sex into preclinical evaluation of novel interventions for neurodegenerative diseases.},
}

Animals
Male
Female
*Neuroprotective Agents/pharmacology
*Withania/chemistry
*Alzheimer Disease/drug therapy/pathology
*Plant Extracts/pharmacology
Mice
Disease Models, Animal
Autophagy/drug effects
Mice, Transgenic
Brain/drug effects/pathology

@article {pmid42885186,
year = {2026},
author = {Joseph, JM and Rachel, J and Han, G and Smith, ML},
title = {Comparing Health Care Utilization Between Medicare Advantage and Traditional Medicare by Dementia Status: A Propensity-Weighted Analysis.},
journal = {Health services research},
volume = {61},
number = {5},
pages = {e70174},
pmid = {42885186},
issn = {1475-6773},
mesh = {Humans ; United States ; Female ; Aged ; *Medicare Part C/statistics & numerical data ; Male ; Cross-Sectional Studies ; *Patient Acceptance of Health Care/statistics & numerical data ; *Dementia/epidemiology/therapy ; *Medicare/statistics & numerical data ; Aged, 80 and over ; Propensity Score ; Alzheimer Disease ; },
abstract = {OBJECTIVE: To compare health care utilization between Medicare Advantage (MA) and Traditional Medicare (TM) beneficiaries, stratified by Alzheimer's disease and related dementias (ADRD) status.

STUDY SETTING AND DESIGN: Repeated cross-sectional observational analysis of community-dwelling Medicare beneficiaries aged ≥ 65 years continuously enrolled in MA or TM. Eight self- or proxy-reported binary utilization outcomes over a 12-month reference period were estimated by survey-weighted linear probability models stratified by ADRD status.

Secondary analysis of pooled 2018-2022 Medicare Current Beneficiary Survey (MCBS) public use files (N = 43,995: 974 TM and 954 MA with ADRD; 23,050 TM and 19,017 MA without ADRD), excluding beneficiaries entitled through disability or end-stage renal disease and records with missing covariates. Dual-eligible beneficiaries were retained and dual eligibility included as a covariate. Stabilized inverse probability of treatment weights multiplied by MCBS full-sample weights addressed non-random MA enrollment.

PRINCIPAL FINDINGS: Among beneficiaries with ADRD, seven of eight adjusted MA - TM differences were not statistically significant. Specialist visits were more common among MA beneficiaries with ADRD (5.2 percentage points; 95% CI, -0.1 to 10.2). Among beneficiaries without ADRD, MA was associated with lower outpatient hospital visits (-2.6; -3.7 to -1.6) and lower reported need for home health visits (-0.9; -1.5 to -0.3). Effect modification by ADRD status was significant only for specialist visits (interaction 6.3 percentage points; p = 0.004).

CONCLUSIONS: Adjusted health care utilization was broadly comparable between MA and TM for beneficiaries with ADRD, with the exception of higher specialist use in MA. Among beneficiaries without ADRD, MA was associated with lower outpatient hospital use. Plan-type differences were smaller and fewer for beneficiaries with ADRD.},
}

Humans
United States
Female
Aged
*Medicare Part C/statistics & numerical data
Male
Cross-Sectional Studies
*Patient Acceptance of Health Care/statistics & numerical data
*Dementia/epidemiology/therapy
*Medicare/statistics & numerical data
Aged, 80 and over
Propensity Score
Alzheimer Disease

@article {pmid42885191,
year = {2026},
author = {Lee, S and Kim, K and Kim, H and Oh, MS and Yoon, K and Kwak, S and Kim, J and Lee, GH and Kim, Y and Kim, J},
title = {Focused Ultrasound as a Plasma Protein Binding-targeted Strategy to Enhance Brain Uptake of Donepezil.},
journal = {Experimental neurobiology},
volume = {},
number = {},
pages = {},
doi = {10.5607/en26028},
pmid = {42885191},
issn = {1226-2560},
abstract = {Donepezil, a reversible acetylcholinesterase inhibitor, is widely used for the symptomatic treatment of Alzheimer's disease (AD). Although higherdose donepezil has been shown to provide additional clinical benefit, dose escalation is often limited by cholinergic adverse effects. Given that approximately 96% of circulating donepezil is bound to plasma proteins, especially albumin, we hypothesized that increasing its unbound fraction from albumin may improve brain delivery without increasing the administered dose. To achieve this goal, herein we examined whether the donepezil-albumin complex can be dissociated by low-intensity focused ultrasound (FUS) in vitro. Then brain uptake of donepezil was evaluated in mice receiving intravenous donepezil followed by targeted brain FUS stimulation. As a result, FUS significantly increased unbound fraction of donepezil at the targeted region in vitro, resulting in a 41.1% increase of donepezil diffusion into dialysis cassettes compared with non-sonicated controls. In mice receiving intravenous donepezil, targeted brain FUS stimulation increased brain donepezil concentrations by 52.7% at 15-min post-administration time. These findings suggest that low-intensity FUS enhances brain uptake of donepezil, potentially through modulation of donepezil-albumin binding, and support further investigation of plasma protein binding-targeted brain drug delivery.},
}

@article {pmid42856725,
year = {2026},
author = {Razavi, A and Tucker, NR and Ghosh, AJ and Faraone, SV and Glatt, SJ and Hess, JL},
title = {Predicting Rates of Cognitive Decline in Older Adults with Brain- and Cardiac-Imputed Transcripts.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
pmid = {42856725},
abstract = {Severe cognitive decline due to dementia is an important clinical indicator signaling neurodegeneration. Predicting cognitive decline rates can be useful in establishing prognosis and modifying treatment regimens. The rate of decline is highly variable across patients with dementia and may be determined by an interplay of many factors. This variability poses challenges to existing tools for predicting disease progression. Changes in heart and brain tissue have been associated with cognitive decline, yet tissue-specific molecular data are difficult to obtain. In this study, we sought to estimate cognitive decline-related transcripts in the brain and heart of people actively living with and without dementia. We reconstructed transcriptomic profiles in brain and heart with the transcriptome-imputation algorithms BrainGENIE and HeartGENIE, and identified several hundreds of transcripts associated with cognitive decline over a two-year assessment window, with the cerebellar hemisphere, left ventricle of the heart, and atrial appendage showing the largest number of cognitive-related transcripts. Pathway analysis revealed an enrichment among cognition-related transcripts of gene sets involved in synaptic, proteostasis/autophagy, immunologic, and mitochondrial respiratory chain functioning. Hundreds of perturbagens show significant concordance with cognitive decline-related transcriptomic signatures in brain and heart, pointing to potentially druggable targets. Top brain- and heart-specific cognition-associated transcripts were incorporated into LASSO regression models predicting future cognitive decline and were compared to two models, one utilizing age, sex and educational attainment, and a hybrid model incorporating both data types. Our models were able to achieve statistically significant correlations in the test set, yet had weak overall. Together, these findings demonstrate that brain and heart transcriptomes capture distinct aspects of biology related to cognitive decline, providing more nuanced insights into normal and aberrant brain aging that may inform drug-repurposing and risk-prediction efforts.},
}

@article {pmid42884062,
year = {2026},
author = {Kuikel, K and McEwen, A and Mathiske, TJ and Wojtaszak, L and John, JAS and Delbaz, A},
title = {Combined Effects of Chlamydia pneumoniae Infection and Hypoxia on Glial Metabolism and Alzheimer's Disease-Related Pathways.},
journal = {International journal of molecular sciences},
volume = {27},
number = {19},
pages = {},
doi = {10.3390/ijms27198820},
pmid = {42884062},
issn = {1422-0067},
support = {//Clem Jones Foundation/ ; //Goda Foundation/ ; },
mesh = {Humans ; *Alzheimer Disease/metabolism/microbiology/pathology ; *Chlamydophila pneumoniae ; Amyloid beta-Peptides/metabolism ; *Neuroglia/metabolism ; Astrocytes/metabolism/microbiology ; Cell Hypoxia ; *Hypoxia/metabolism ; Microglia/metabolism/microbiology ; Cell Line ; Proteomics/methods ; *Chlamydophila Infections/metabolism ; *Chlamydia Infections/metabolism ; },
abstract = {Alzheimer's disease involves complex interactions among neuroinflammation and metabolic dysfunction. Emerging evidence implicates microbial pathogens and hypoxia as converging stressors, yet their combined impact on glial function remains poorly understood. Human astrocyte and microglial cell lines were exposed to four experimental conditions: (i) normoxic control, (ii) Chlamydia pneumoniae infection under normoxia, (iii) hypoxia control and (iv) Chlamydia pneumoniae infection under hypoxic conditions. Hypoxia was induced at 3% oxygen for 72 h. Cellular responses were assessed using NanoString nCounter transcriptomics using the Alzheimer's Disease and Metabolic Pathways panels, Tandem Mass Tag proteomics, MTT reduction, glucose uptake, intracellular ATP quantification and amyloid beta quantification by ELISA. Combined exposure to infection and hypoxia was associated with cell-type-specific alterations in glial metabolic and transcriptional responses. Factorial transcriptomic analysis identified significant infection × oxygen interactions across both NanoString panels and glial cell types. Proteomic responses differed according to cell type and oxygen availability. Aβ40 and Aβ42 measurements demonstrated treatment-associated alterations in the extracellular Aβ peptide profile, including increased Aβ42/Aβ40 ratios following infection. Together, these findings demonstrate distinct and interacting effects of infection and hypoxia on glial metabolic and molecular responses and identify Alzheimer's disease-related cellular changes warranting further investigation in physiologically relevant models.},
}

Humans
*Alzheimer Disease/metabolism/microbiology/pathology
*Chlamydophila pneumoniae
Amyloid beta-Peptides/metabolism
*Neuroglia/metabolism
Astrocytes/metabolism/microbiology
Cell Hypoxia
*Hypoxia/metabolism
Microglia/metabolism/microbiology
Cell Line
Proteomics/methods
*Chlamydophila Infections/metabolism
*Chlamydia Infections/metabolism

@article {pmid42879726,
year = {2026},
author = {Reynolds, EL and Elafros, MA and Muthukumar, L and Shippey, E and Budhu, JA and Terman, SW and Burke, JF and Callaghan, BC},
title = {Predictors of Antiamyloid Medication Utilization and Adherence Among People With Alzheimer Disease and Mild Cognitive Impairment.},
journal = {Neurology},
volume = {107},
number = {9},
pages = {e218594},
doi = {10.1212/WNL.0000000000218594},
pmid = {42879726},
issn = {1526-632X},
mesh = {Humans ; Female ; *Alzheimer Disease/drug therapy ; Male ; Aged ; *Cognitive Dysfunction/drug therapy ; Aged, 80 and over ; Antibodies, Monoclonal, Humanized/therapeutic use ; *Drug Monitoring ; *Medication Adherence ; },
abstract = {BACKGROUND AND OBJECTIVES: From 2021 to 2024, 3 amyloid monoclonal antibody medications (aducanumab, lecanemab, and donanemab) were approved by the US Food and Drug Administration for treatment of mild cognitive impairment (MCI) and mild dementia due to Alzheimer disease (AD). We determined the demographics and social drivers of health associated with utilization and initial adherence of these medications.

METHODS: We used the Vizient database to identify patients with MCI or dementia using an ICD-10 coding definition. Propensity score matching was used to match patients who received an antiamyloid medication to those who did not, based on date of MCI/dementia diagnosis and follow-up. Social drivers of health were assessed using the Vizient Vulnerability Index (VVI), a neighborhood-level measure of socioeconomic vulnerability. Logistic regression determined associations between demographics, Elixhauser comorbidity, and VVI, with utilization of antiamyloid medications. Poisson regression determined associations between demographic, Elixhauser comorbidity, and VVI and initial adherence (measured as days supplied) of antiamyloid medications.

RESULTS: We identified 1,198,362 participants with MCI/dementia, of whom 2,427 (0.2%) were prescribed an antiamyloid medication. Of those prescribed an antiamyloid medication, 1,696 (69.9%) were matched to participants with MCI/dementia that were not prescribed antiamyloid medications (mean age 75.5 [SD 9.5], 56.1% female, 80.1% non-Hispanic White). We found that higher age (odds ratio [OR] 0.93, 95% CI 0.92-0.94), higher Elixhauser comorbidity index (OR 0.56, 95% CI 0.52-0.59), being non-Hispanic Black (OR 0.14, 95% CI 0.09-0.23), and being Hispanic (OR 0.21, 95% CI 0.13-0.36) associated with lower odds of receiving an antiamyloid medication. Furthermore, having greater VVI was associated with lower odds of receiving an antiamyloid medication. By contrast, only higher Elixhauser comorbidity score was associated with lower initial medication adherence (rate ratio 0.94, 95% CI 0.93-0.96), but not age, sex, race/ethnicity, and overall vulnerability.

DISCUSSION: We found that younger, non-Hispanic White patients, with fewer comorbidities, and lower vulnerability, were more likely to receive antiamyloid medications. By contrast, among patients receiving an antiamyloid medication, only higher comorbidity score associated with lower initial medication adherence. These findings indicate a potential disparity in medication access for US patients with MCI/dementia that could become problematic barriers to care as medications for dementia continue to evolve.},
}

Humans
Female
*Alzheimer Disease/drug therapy
Male
Aged
*Cognitive Dysfunction/drug therapy
Aged, 80 and over
Antibodies, Monoclonal, Humanized/therapeutic use
*Drug Monitoring
*Medication Adherence

@article {pmid42880054,
year = {2026},
author = {Benussi, A and Agosta, F and Agnello, L and Alfano, AR and Altini, M and Antico, A and Basilico, S and Bellelli, G and Bonanni, L and Bottini, G and Bozzali, M and Brignoli, O and Bruno, G and Cagnin, A and Calloni, SF and Cappa, SF and Caraci, F and Cecchin, D and Ciaccio, M and Cocozza, S and Cosottini, M and De Leo, D and Falini, A and Gaetani, L and Gandolfo, N and Gotta, F and Lodi, R and Logroscino, G and Marcello, E and Marra, C and Marrocco, W and Morbelli, S and Mecocci, P and Mossello, E and Palleschi, L and Palumbo, P and Pantoni, L and Parnetti, L and Roccatagliata, L and Sorbi, S and Spadin, P and Splendiani, A and Tessitore, A and Ungar, A and Zappalà, G and Padovani, A},
title = {Updated Italian intersocietal recommendations for the appropriate use of anti-amyloid monoclonal antibodies in Alzheimer's disease.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {10},
pages = {100685},
doi = {10.1016/j.tjpad.2026.100685},
pmid = {42880054},
issn = {2426-0266},
abstract = {With the European authorisation of lecanemab and donanemab, Italy is entering the era of disease-modifying therapy for early symptomatic Alzheimer's disease. The Italian Expert Panel on Alzheimer (EPA), which convened 21 scientific societies and patient associations and published a first set of intersocietal recommendations in 2025, was reconvened in Rome on 24 January 2026 (EPA2) to address the operational gaps that had emerged during the implementation of that document. A modified Delphi process was adopted to formalise consensus on the most controversial points raised during the meeting. Thirty-six declarative statements covering five domains, namely the tiered organisation of the Centres for Cognitive Disorders and Dementia (CDCD), clinical staging and treatment monitoring, eligibility considerations in mild cognitive impairment and atypical phenotypes, composition of the multidisciplinary team, and magnetic resonance imaging thresholds, ARIA monitoring and biomarker pathway, were submitted to a multidisciplinary panel of experts. Strong agreement was reached on the large majority of statements, providing quantitative endorsement for a competence-based reorganisation of the CDCD network, the harmonised use of the Clinical Dementia Rating, an explicit composition of the multidisciplinary team, trial-aligned magnetic resonance imaging eligibility criteria with a move towards risk-adapted ARIA monitoring, and a stepwise biomarker pathway integrating plasma assays, cerebrospinal fluid analysis on automated platforms and amyloid positron emission tomography. The document provides Italian regional and national health systems, prescribing centres and reimbursing authorities with a quantitative blueprint for the appropriate, equitable and sustainable use of anti-amyloid monoclonal antibodies in clinical practice.},
}

@article {pmid42880601,
year = {2026},
author = {Barberà-Parada, S and Biosca-Brull, J and Gabaldón-Díaz, R and Rodulfo-Cárdenas, R and Guardia-Escoté, L and Blanco, J and Cabré, M and Colomina, MT},
title = {Sex-divergent vulnerability to chronic peripheral LPS challenge in aged ApoE4 mice: Male systemic fragility versus female central neuroinflammation.},
journal = {Behavioural brain research},
volume = {517},
number = {},
pages = {116524},
doi = {10.1016/j.bbr.2026.116524},
pmid = {42880601},
issn = {1872-7549},
abstract = {Inflammageing links chronic inflammation to biological aging, contributing to senescence and multimorbidity common in the elderly. In neurodegenerative diseases, such as Alzheimer's disease, inflammatory processes play a causal role in accelerating neurodegeneration. Interestingly, apolipoprotein E (APOE), particularly the APOEε4 allele, is a major genetic risk factor for neurodegeneration, acting as a key immunomodulator with sex differences. This is especially relevant given the lack of clear prevention strategies for APOEε4 carriers. Therefore, this study characterized the sex-specific neuroinflammatory and cognitive vulnerability of APOE4 genotype under a chronic lipopolysaccharide (LPS) challenge in senescence-transition stage. Male and female homozygous apoE4 mice (15-16 months old) were administered intraperitoneal doses of 0 or 0.25 mg/kg LPS three times per week for a total of 17 doses. Body weight was monitored, and behavioural assessments were conducted from the 12th injection until the 17th. Serum and tissues were collected to assess hippocampal, cortical and systemic markers of inflammation, antioxidant-related genes, genes implied in myelin dynamics, and neurotrophin-related transcripts. Findings revealed basal sex-dependent divergent phenotypes with specific responses under LPS challenge. Under LPS treatment, males exhibited higher systemic fragility, with significantly increased mortality, which may have conditioned cognitive outcomes. Females showed greater central alterations related to neuroinflammation along with altered expression of myelin-related transcripts. However, the results suggest a stablished tolerance to LPS. These results highlight how chronic systemic inflammation during ageing in an APOE4 genotype background shapes sex-divergent pathological trajectories, underscoring the need to address sex-specific therapeutic strategies.},
}

@article {pmid42882500,
year = {2026},
author = {Alam, JJ and Germann, UA and Maruff, P},
title = {Targeting Pro-Inflammatory Interleukin-1 Beta Signaling to Modulate Neuroinflammatory Processes Associated with Cognitive Decline in Dementia with Lewy Bodies.},
journal = {Cells},
volume = {15},
number = {19},
pages = {},
doi = {10.3390/cells15191803},
pmid = {42882500},
issn = {2073-4409},
support = {//CervoMed Inc/ ; #R01AG080536/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Interleukin-1beta/metabolism ; *Lewy Body Disease/drug therapy/complications/metabolism ; *Signal Transduction/drug effects ; *Neuroinflammatory Diseases/metabolism/drug therapy ; *Cognitive Dysfunction/drug therapy/complications/metabolism ; Amyloid beta-Peptides ; Female ; Alzheimer Disease/drug therapy ; Male ; Interleukin-6/metabolism ; },
abstract = {Interleukin-1 beta (IL-1β) is implicated as a molecular driver of cognitive decline in Alzheimer's disease (AD) and dementia with Lewy bodies (DLB), potentially through activation of pro-inflammatory pathways within the neuron that impair synaptic function. Because pro-inflammatory IL-1β signaling depends on p38α kinase, the oral brain-penetrant p38α inhibitor neflamapimod has the potential to reverse synaptic dysfunction and treat cognitive decline in these contexts. Neflamapimod has also shown positive effects in animal models and in clinical studies in AD and DLB. Herein we evaluated neflamapimod effects on pro-inflammatory IL-1β signaling in vitro and in patients with AD or DLB. In human PBMCs, neflamapimod inhibited IL-1β-induced IL-6 and IL-8 production with EC50 values of 6.3 ± 1.3 nM and 7.1 ± 3.2 nM, respectively. In AD, six weeks of neflamapimod 40 mg BID treatment reduced CSF levels of IL-6 and IL-8, with maximal effects at trough drug concentration ≥4 ng/mL (9 nM). In DLB, neflamapimod 40 mg TID increased the plasma Aβ42/40 ratio and reduced plasma GFAP levels, treatment effects consistent with reduced pro-inflammatory IL-1β signaling. Collectively, these results support the hypothesis that inhibition of p38α-dependent IL-1β signaling may beneficially modulate neuroinflammatory processes that otherwise are associated with cognitive decline in DLB, and potentially in AD.},
}

Humans
*Interleukin-1beta/metabolism
*Lewy Body Disease/drug therapy/complications/metabolism
*Signal Transduction/drug effects
*Neuroinflammatory Diseases/metabolism/drug therapy
*Cognitive Dysfunction/drug therapy/complications/metabolism
Amyloid beta-Peptides
Female
Alzheimer Disease/drug therapy
Male
Interleukin-6/metabolism

@article {pmid42883332,
year = {2026},
author = {Işık, M and Syla, GH and Karakaya, A and Çevik, UA and Daoud, NE and Fırat, M and Öğünç Keçeci, Y and Özkay, Y and Kaplancıklı, ZA and Beydemir, Ş},
title = {Design and Synthesis of New Thiazole Derivatives for Alzheimer's Disease Therapy as a Potential Cholinesterase Inhibitor; Toxicity Prediction and Molecular Docking Studies and Biological Evaluation.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {19},
pages = {},
doi = {10.3390/molecules31193568},
pmid = {42883332},
issn = {1420-3049},
support = {//Anadolu University/ ; },
mesh = {*Cholinesterase Inhibitors/chemistry/chemical synthesis/pharmacology ; Molecular Docking Simulation ; *Thiazoles/chemistry/chemical synthesis/pharmacology ; *Alzheimer Disease/drug therapy/enzymology ; Humans ; Butyrylcholinesterase/chemistry/metabolism ; Acetylcholinesterase/chemistry/metabolism ; *Drug Design ; Structure-Activity Relationship ; Molecular Structure ; Animals ; },
abstract = {In this study, thiazole derivatives 13-23 were synthesized as novel cholinesterase inhibitors. Their structures were elucidated using [1]H-NMR, [13]C-NMR, and elemental analysis techniques. The binding positions and efficiencies of the designed compounds on the enzyme were investigated through molecular docking studies, and the properties of ADMET were examined using computational methods. Cytotoxicity analyses of the synthesized compounds were performed to screen their inhibitory effects on acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in vitro. It has been determined that these compounds do not exhibit a significant cytotoxic effect on healthy endothelial cells. Although the compounds showed lower efficacy in AChE inhibition compared to the reference compound tacrine (IC50: 0.136 μM; KI: 0.46 ± 0.01 nM), they exhibited moderate inhibitory effects. Among these, compounds 16 and 23 were found to be the most potent AChE inhibitors, with IC50 values of 36.47 µM and 34.65 µM, and KI values of 22.20 ± 1.23 and 21.10 ± 1.58 µM, respectively, while compounds 15 and 20 were found to be the most potent BChE inhibitors, with IC50 values of 17.76 µM and 16.90 µM, and KI values of 14.10 ± 0.58 and 13.40 ± 0.48 µM, respectively, on other cholinesterases. These tested compounds can be considered potential candidates for further research in the treatment of Alzheimer's disease (AD).},
}

*Cholinesterase Inhibitors/chemistry/chemical synthesis/pharmacology
Molecular Docking Simulation
*Thiazoles/chemistry/chemical synthesis/pharmacology
*Alzheimer Disease/drug therapy/enzymology
Humans
Butyrylcholinesterase/chemistry/metabolism
Acetylcholinesterase/chemistry/metabolism
*Drug Design
Structure-Activity Relationship
Molecular Structure
Animals

@article {pmid42883911,
year = {2026},
author = {Rojas-Sánchez, I and Cortes-Flores, E and Camacho-Concha, N and Almazán, JL and Ramírez-Lugo, L and Crivelli-Galindo, E and Ramirez-Serrano, CE and Pedraza-Alva, G and Pérez-Martínez, L},
title = {Therapeutic Administration of Malva parviflora Hydroalcoholic Extract Restores Cognitive Function Consistent with a Resilient Phenotype in Female 5XFAD.},
journal = {International journal of molecular sciences},
volume = {27},
number = {19},
pages = {},
doi = {10.3390/ijms27198665},
pmid = {42883911},
issn = {1422-0067},
support = {PAPIIT IN217822//Dirección General de Asuntos del Personal Académico (DGAPA), Universidad Nacional Autónoma de México (UNAM)/ ; PAPIIT IN222925//Dirección General de Asuntos del Personal Académico (DGAPA), Universidad Nacional Autónoma de México (UNAM)/ ; PAPIIT IN216922//Dirección General de Asuntos del Personal Académico (DGAPA), Universidad Nacional Autónoma de México (UNAM)/ ; CBF2023-2024-878//Consejo Nacional de Humanidades, Ciencias y Tecnologías/ ; IFC 2016-2282//Consejo Nacional de Humanidades, Ciencias y Tecnologías/ ; },
mesh = {Animals ; Female ; *Plant Extracts/pharmacology/chemistry/administration & dosage ; *Cognition/drug effects ; *Alzheimer Disease/drug therapy/metabolism ; Mice ; Hippocampus/drug effects/metabolism ; Amyloid beta-Peptides/metabolism ; *Malva/chemistry ; Mice, Transgenic ; Long-Term Potentiation/drug effects ; Phenotype ; Disease Models, Animal ; Glial Fibrillary Acidic Protein/metabolism ; Neuronal Plasticity/drug effects ; },
abstract = {The remarkable increase in human life expectancy has been accompanied by a rising global incidence of neurodegenerative disorders, particularly Alzheimer's disease. This condition is characterized by progressive accumulation of soluble and insoluble amyloid-beta peptides, neuroinflammation, and synaptic dysfunction in the hippocampus, leading to impaired higher-order cognition. Epidemiological evidence indicates that women are disproportionately affected; however, female-specific pathology remains understudied. Here, we evaluated the therapeutic potential of a hydroalcoholic extract of Malva parviflora in female 5XFAD mice following prolonged intragastric administration initiated after disease establishment. Long-term treatment shifted cognitive performance toward a phenotype comparable to wild-type littermates, an improvement associated with reduced soluble amyloid-beta levels in the hippocampus and peripheral circulation, and significant attenuation of reactive astrogliosis as evidenced by reduced hippocampal glial fibrillary acidic protein levels. Because reactive astrocytes impair synaptic activity and metabolic homeostasis during disease progression, we examined the direct effects of Malva parviflora on synaptic plasticity ex vivo. Incubation of hippocampal synaptosomes from adult female 5XFAD mice with the extract restored chemically induced long-term potentiation. These findings demonstrate that Malva parviflora attenuates key pathological hallmarks of Alzheimer's disease and promotes cognitive recovery, supporting its potential as a plant-derived therapeutic candidate, particularly in females most affected by Alzheimer's disease. Future studies including both sexes under a therapeutic paradigm are needed to determine the generalizability of these findings.},
}

Animals
Female
*Plant Extracts/pharmacology/chemistry/administration & dosage
*Cognition/drug effects
*Alzheimer Disease/drug therapy/metabolism
Mice
Hippocampus/drug effects/metabolism
Amyloid beta-Peptides/metabolism
*Malva/chemistry
Mice, Transgenic
Long-Term Potentiation/drug effects
Phenotype
Disease Models, Animal
Glial Fibrillary Acidic Protein/metabolism
Neuronal Plasticity/drug effects

@article {pmid42877349,
year = {2026},
author = {Yuan, X and Tang, Q and Wang, T},
title = {Screening of herbs for vascular dementia: Through the combination of reverse network pharmacology and traditional Chinese medicine enrichment analysis.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261466619},
pmid = {42877349},
issn = {2542-4823},
abstract = {BACKGROUND: Vascular dementia (VaD) represents the second most prevalent form of cognitive impairment following Alzheimer's disease. Its pathological mechanisms encompass a complex interplay of cerebral ischemia, inflammatory responses, oxidative stress, and neuronal apoptosis. Current clinical interventions predominantly target cerebral circulation enhancement and neuroprotection; however, these approaches exhibit limitations in efficacy, single-target specificity, and significant adverse effects. Traditional Chinese medicine (TCM) offers a novel therapeutic paradigm for complex diseases owing to its multi-target synergistic effects, low toxicity profile, and integrated preventive and therapeutic benefits.

OBJECTIVE: This study aims to identify the potentially effective active components in TCM targeting VaD, and to elucidate the multi-target regulatory mechanisms.

METHODS: This study employed a "disease-gene-drug" reverse screening model, integrating bioinformatics and network pharmacology, to systematically identify potential TCM candidates for VaD treatment and elucidate their multi-target regulatory mechanisms.

RESULTS: A total of eight TCM agents with potential VaD therapeutic efficacy (including Niuxi, Pueraria lobata, and Citrus aurantium) were identified, alongside nine active compounds and nine therapeutic targets. Notably, Gehua and Zhike were reported for the first time to exhibit potential VaD therapeutic effects. Furthermore, molecular docking technology was utilized to investigate the binding affinity and interaction modes of these nine active compounds with key targets.

CONCLUSIONS: To our knowledge, this study is among the first to apply reverse network pharmacology combined with TCM enrichment specifically to VaD.},
}

@article {pmid42877369,
year = {2026},
author = {Shrestha, N and Chiang, C and Wei, YJ},
title = {Central nervous system-active medication polypharmacy and risk for nursing home admission among adults with early-onset dementia: A retrospective cohort study.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261472831},
pmid = {42877369},
issn = {2542-4823},
abstract = {BACKGROUND: While central nervous system (CNS)-active medication polypharmacy is prevalent among adults with early-onset dementia (EOD), its impact on nursing home (NH) admission is unclear.

OBJECTIVE: To examine whether CNS-active medication polypharmacy is associated with risk for NH admission among patients with EOD.

METHODS: A retrospective cohort study using 2012-2021 MarketScan Databases was conducted with adults aged 30 to 64 years diagnosed with Alzheimer's disease and related dementias (ADRD). CNS-active medication polypharmacy was assessed during a fixed 6-month period after an indexed ADRD diagnosis and defined as concurrent use of ≥3 CNS-active medications on the American Geriatrics Society Beers Criteria list that overlapped for ≥30 consecutive days. Cox hazards models were used to estimate the hazard ratio (HR) of NH admission between patients with versus without CNS-active medication polypharmacy, with adjustment for baseline covariates via inverse probability of treatment weighting.

RESULTS: Of the 18,029 patients with EOD identified, those with CNS-active medication polypharmacy (versus those without) had an increased risk of NH admission (HR, 1.34 [95% CI, 1.16-1.56]). The risk was pronounced in patients aged >50 years, male patients, patients with a diagnosis of Alzheimer's disease or senile dementia, and patients having baseline use of anti-dementia medications.

CONCLUSIONS: In this commercially insured population of adults with EOD, receipt of CNS-active medication polypharmacy was associated with risk for NH admission. The finding, however, should be interpreted with caution, as it may reflect differences in the underlying disease severity and clinical indications treated by the studied CNS-active medications.},
}

@article {pmid42877383,
year = {2026},
author = {Ferrer, A and Moon, J},
title = {Lecanemab real-world treatment outcomes from cohort study in early Alzheimer's disease.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261470042},
pmid = {42877383},
issn = {2542-4823},
abstract = {Lecanemab has demonstrated amyloid reduction and slowed clinical decline in early Alzheimer's disease trials. Herein, we report retrospective case series results on lecanemab treatment in our clinic. Overall, 61 individuals were included. For the 33 patients with Kokmen Mental Status Exam baseline and post-baseline scores, 67% had either improved or stable scores. Nine incident amyloid-related imaging abnormalities were observed with all but one patient continuing treatment. Six patients were safely transitioned from aducanumab to lecanemab treatment upon market withdrawal of aducanumab. In a real-world clinical practice setting, the lecanemab effectiveness and safety profile were similar to that observed in clinical studies.},
}

@article {pmid42877391,
year = {2026},
author = {Granadillo, E and Peterson, A and Bloyer, E and Hancock, LM and Shah-Basak, P and Kraegel, P and Schold, S and Okonkwo, O and Nair, VA and Prabhakaran, V and Ikonomidou, C},
title = {Multifield extended high-definition transcranial direct current stimulation in mild cognitive impairment: A proof-of-concept study on cognition and brain network connectivity.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261449802},
pmid = {42877391},
issn = {2542-4823},
abstract = {BACKGROUND: Treatment of mild cognitive impairment (MCI) could delay the progression of cognitive decline. Noninvasive neuromodulation might restore brain plasticity and lead to clinically meaningful cognitive improvements.

OBJECTIVE: To investigate feasibility and tolerability of a multi-field (four regions) extended (80-min-long) intervention using high-definition transcranial direct current stimulation (HD-tDCS) combined with computerized cognitive training (CCT) in participants with MCI and to explore its effects on cognition and brain functional connectivity.

METHODS: Double-blinded, randomized proof-of-concept trial of daily sham HD-tDCS + CCT (n = 4) or anodal HD-tDCS + CCT (n = 4) for 15 sessions over 3 months. Four cortical regions were targeted using neuronavigation, including putative frontal coordinates of cognitive reserve and lateral parietal coordinates hypothesized to have robust hippocampal connectivity. Neurocognitive outcomes were assessed at 3 and 6 months and resting-state functional connectivity changes were evaluated at 3 months. Statistical analysis included independent sample t-tests, Wilcoxon rank-sum tests, and Bonferroni correction for multiple comparisons.

RESULTS: Eleven subjects were eligible and interviewed, and 8 consented (73% consent rate). All 8 completed the trial with only minor adverse events (100% completion rate). Blinding was successful. A large but non-significant increase in Alzheimer's Disease Cooperative Study-Preclinical Alzheimer's Cognitive Composite scores at 6 months was observed in the anodal group (59.8%) compared with sham (24.5%). Significant declines were seen in left parietal cortex-left caudal hippocampus connectivity (p = 0.004) and right intraparietal sulcus-right frontal eye fields connectivity (p = 0.039) in the anodal group.

CONCLUSIONS: The intervention was feasible and well tolerated. Findings suggest possible normalization of aberrant or compensatory hyperconnectivity in MCI. Larger studies are needed.Clinical Trial Number: NCT04246164.},
}

@article {pmid42877397,
year = {2026},
author = {Yano, K and Nagata, T and Nakajima, S and Kito, S and Shinagawa, S},
title = {The trajectory of delusions in patients with Alzheimer's disease receiving pharmacological treatment: A re-analysis of data from the CATIE-AD trial.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261494480},
pmid = {42877397},
issn = {2542-4823},
abstract = {BACKGROUND: Previous studies have reported decreases in the proportion of patients with delusions and severity of delusions during long-term follow-up in Alzheimer's disease (AD).

OBJECTIVE: The aim of the present study was to explore clinical predictors of the disappearance of delusions in AD patients enrolled in the Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer's Disease (CATIE-AD) trial who received pharmacological treatment.

METHODS: We re-analyzed the data of 421 clinic-based patients enrolled in the CATIE-AD trial to examine the association between the disappearance of delusions and relevant factors selected by reference to previous studies at week 12, 24, and 36 of treatment. Generalized Estimating Equations were used to analyze the impact of the assigned medication (mainly atypical antipsychotics), treatment duration, and their interaction on the disappearance of delusions over time.

RESULTS: The proportion of patients with delusions (PWD) gradually decreased to approximately 50% over the 36-week treatment period; however, no significant differences in the baseline variables were identified between the PWD and patients without delusions (POD) at any of the follow-up time-points (weeks 12, 24, or 36). Furthermore, the treatment duration was found to contribute significantly to the disappearance of delusions over time (conversion from PWD at baseline to POD at subsequent follow-up visits), independent of active drug use.

CONCLUSIONS: Disappearance of delusions in AD patients was associated with the interval from the baseline, regardless of the use of active drugs. Insights into the natural course of delusions could guide clinicians toward selecting alternative treatment strategies for patients with AD.},
}

@article {pmid42877407,
year = {2026},
author = {Horowitz, R},
title = {Improving biomarkers of inflammation including phosphorylated tau in a patient with chronic Lyme disease/post-treatment Lyme disease syndrome using dapsone combination therapy: A case study and literature review.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261445434},
pmid = {42877407},
issn = {2542-4823},
abstract = {BACKGROUND: Borrelia burgdorferi, the agent of Lyme disease, has been found to co-localize in Alzheimer's disease autopsy brain tissues with biofilm, amyloid, and phosphorylated tau.

OBJECTIVE: To determine whether dapsone combination therapy (DCT), a biofilm/persister antibiotic regimen with good central nervous system penetration can improve p-tau and peripheral inflammatory markers in a patient with chronic Lyme disease (CLD)/post-treatment Lyme disease syndrome (PTLDs).

METHODS: A 67-year-old female with CLD/PTLDs, and Ehrlichia, Babesia, Bartonella, and Coxiella burnetii had a 15-year history of joint pain with inflammation and mild cognitive impairment despite prior treatment with doxycycline. She was checked for changes in peripheral inflammation, i.e., rheumatoid factors (RFs) and changes in serum p-tau181, p-tau 217, and amyloid-β (Aβ) 42:40 ratios before and after treatment with DCT.

RESULTS: Elevated RFs at 20 IU/mL decreased into normal range three months post treatment accompanied by a decrease in pain with improved flexibility. An initially elevated serum p-tau 217 level in the blood at 0.33 pg/mL (normal range <0.15 pg/mL) prior to using DCT normalized, decreasing to 0.12 pg/mL three months post therapy, while p-tau 181 levels remained within normal limits. Aβ ratios simultaneously improved post DCT increasing from 0.185 pg/mL to 0.216 (normal range >0.170) accompanied by subjective improvements in concentration and recall.

CONCLUSIONS: This is the first case study proving that a short term, biofilm/persister drug regimen, i.e., DCT, can potentially improve peripheral autoantibodies (RFs) and pathological triggers of neuroinflammation (p-tau, Aβ) in a patient with CLD/PTLDs.},
}

@article {pmid42877439,
year = {2026},
author = {Su, CY and Wong, YS and Lee, C and Sung, SF and Wu, CS and Su, YH and Lin, MH and Ong, CT},
title = {Higher thyroid-stimulating hormone level may delay dementia progression in patients without thyroid dysfunction.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261494184},
pmid = {42877439},
issn = {2542-4823},
abstract = {BACKGROUND: Although thyroid dysfunction causes reversible cognitive impairment, the role of thyroid-stimulating hormone (TSH) variation within the normal range in dementia progression remains unclear.

OBJECTIVE: To evaluate the association between baseline euthyroid TSH levels and cognitive decline rate in dementia patients.

METHODS: We conducted a retrospective cohort study using Taiwan's Ditmanson Research Database (2015-2022). Dementia patients with normal thyroid function who initiated anti-dementia medication were included; those with overt thyroid disease, malignancy, or CNS infections were excluded. Baseline TSH (within 180 days prior to treatment) was stratified by the cohort median (1.392 μIU/mL) into Low and High TSH groups. Longitudinal cognitive outcomes were tracked via repeated Mini-Mental State Examination (MMSE) scores over 3 years. Generalized estimating equation (GEE) models evaluated the TSH-cognitive decline association, adjusting for age, sex, baseline MMSE, medication class, and vascular comorbidities.

RESULTS: A total of 402 patients (955 MMSE observations) were analyzed. Baseline characteristics were comparable between groups. In adjusted analyses, the Low TSH group declined by 1.44 MMSE points per year (95% CI: -1.90 to -0.97; p < 0.001). A significant time-by-TSH group interaction (beta = 0.76, 95% CI: 0.17 to 1.34; p = 0.011) indicated a slower annual decline in the High TSH group (-0.68 points/year).

CONCLUSIONS: Among euthyroid dementia patients, higher baseline TSH levels within the reference range were associated with significantly slower cognitive decline. These findings suggest physiological TSH variations may influence neurodegenerative progression, warranting further prospective research to clarify causality.},
}

@article {pmid42877443,
year = {2026},
author = {Lusk, JB and Fitch, KV and Johnson, KG and Liu, A and Lund, JL and Thomas, LE and McDevitt, R and Zhao, A and Whitson, HE and O'Brien, R and Aymes, S and Hammill, BG and Mac Grory, B and Li, F and O'Brien, EC},
title = {Uptake and safety profile of anti-amyloid immunotherapies in routine clinical practice.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261483526},
pmid = {42877443},
issn = {2542-4823},
abstract = {BACKGROUND: Anti-amyloid immunotherapies are approved by the United States Food and Drug Administration for the treatment of Alzheimer's disease; however, the adoption and safety profile of these medications in routine clinical practice have not been described.

OBJECTIVE: To describe the adoption and safety profile of anti-amyloid immunotherapies in routine clinical practice.

METHODS: This was a retrospective observational cohort study using target trial emulation methods. The data source was nationwide electronic health record data from Epic Cosmos. The primary exposure was the first prescription of anti-amyloid immunotherapy versus the active comparator of oral dementia therapy (acetylcholinesterase inhibitor (AChEI) or memantine, selected to minimize bias by baseline health status and disease severity). The primary end point was time to first nontraumatic intracranial hemorrhage (ICH). Propensity score overlap weighting was used to balance baseline demographic and clinical characteristics across treatment groups.

RESULTS: Between July 1, 2023 and January 1, 2025, 2616 patients (median age 74.8 years [IQR 69.8-78.8]; 53.9% female) were prescribed anti-amyloid immunotherapy (with or without AChEI/memantine), and 1,065,192 patients (median age 79.98 [IQR 73.6-85.6], 57.9% female) were prescribed AChEI/memantine alone. In total, 401 patients prescribed anti-amyloid immunotherapy and 274,470 patients prescribed AChEI/memantine were assessed for safety endpoints. Compared with AChEI/memantine, the analysis did not detect a statistically significant association between prescription of anti-amyloid immunotherapy and ICH (owHR 0.73 [95% CI 0.10-5.12]).

CONCLUSIONS: The study did not detect a statistically significant association between prescription of anti-amyloid immunotherapy and ICH. The small treated cohort and low event count yielded imprecise estimates; these findings do not confirm safety and cannot exclude a clinically important increase in risk.},
}

@article {pmid42877463,
year = {2026},
author = {Takahashi, Y and Shiraishi, N and Tsukahara, A and Matsuda, Y and Nishina, T and Yoshikawa, H and Uzu, T and Mori, E},
title = {Symptomatic lobar intracerebral hemorrhage during extended lecanemab treatment: A case report.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261487915},
pmid = {42877463},
issn = {2542-4823},
abstract = {Lecanemab is an anti-amyloid-β protofibril antibody that slows cognitive decline in early Alzheimer's disease. Although amyloid-related imaging abnormalities (ARIA) occur predominantly early in treatment, reports of hemorrhagic events during extended treatment beyond 18 months remain limited. A 77-year-old woman completed a standard 1.5-year lecanemab regimen without ARIA on surveillance MRIs. The day after her 42nd infusion, she acutely developed confusion and incomprehensible speech. MRI revealed a 2.5-cm left parietal subcortical hemorrhage. This case highlights that symptomatic lobar hemorrhage may occur even during extended lecanemab therapy, underscoring the importance of continued safety monitoring during extended treatment.},
}

@article {pmid42877495,
year = {2026},
author = {Cabrera-Martín, MN and Aguiar-Fernández, P and Camacho-Martí, V and Guillén-Valderrama, EF and Jiménez-Bonilla, JF and Lojo-Ramírez, JA and López-Mora, DA and Matías-Guiu, JA and Paredes-Rodríguez, P and Perissinotti, A and Arbizu, J},
title = {Current use and perspectives of PET imaging in Alzheimer's disease: A Spanish national survey.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261437129},
pmid = {42877495},
issn = {2542-4823},
abstract = {BACKGROUND: Novel therapies for Alzheimer's disease are expected to increase the demand for biomarkers. PET will likely play a central role in patient selection and treatment monitoring, requiring adequate infrastructure and trained professionals.

OBJECTIVE: To assess the current status of Nuclear Medicine departments in Spain regarding organization, expertise, and available infrastructure.

METHODS: We conducted a nationwide survey among Nuclear Medicine departments in Spain.

RESULTS: Respondents averaged 19.8 years of professional experience; 62.0% had specific neuroimaging training and 76.0% reported high confidence in amyloid PET interpretation. Hospitals were mainly public (70.6%) and widely distributed geographically, and 73.0% reported having cognitive impairment units. Following the INVEAT plan, Spain currently has 147 PET scanners, although capacity varies: most centers operate one scanner and five reported having none. Amyloid PET is available in 77.0% of departments, with annual volumes ranging from fewer than 10 to more than 100 studies; 15.0% cannot perform amyloid PET due to regional limitations. Quantification tools are available in 41.3% of centers, although only 15.5% include quantitative metrics in reports, while 66.7% support the use of centiloid standardization. Nearly all respondents anticipate increased indications for amyloid PET (screening 83.7%; monitoring 68.5%) and support multidisciplinary collaboration (89.1% favor Neuroimaging Committees). About half report workforce needs, mainly nuclear medicine physicians (46.2%). Research activity in Alzheimer's disease is expected to increase (95.6%).

CONCLUSIONS: Most departments recognize the key role of amyloid PET for anti-amyloid therapy implementation and anticipate increased demand, highlighting the need to expand availability, implement quantification tools, and strengthen multidisciplinary collaboration.},
}

@article {pmid42877510,
year = {2026},
author = {Abdelkader, MS and Atalah, HN and Mamdouh, A and Ghazal, R and Bakr, M and Salama, M},
title = {Retinal tau imaging and histopathology as emerging Alzheimer's disease biomarkers: A systematic review.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823251391710},
pmid = {42877510},
issn = {2542-4823},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) deposition and tau protein aggregation. The retina, as an extension of the central nervous system, has emerged as a promising site for detecting biomarkers of AD.

OBJECTIVE: This systematic review synthesizes the current evidence on retinal tau protein as a diagnostic tool for AD and related tauopathies.

METHODS: This systematic review adhered to PRISMA guidelines, analyzing studies on retinal tau biomarkers, structural changes, and diagnostic imaging techniques. The included studies encompassed molecular investigations, experimental models, and clinical imaging approaches.

RESULTS: Retinal phosphorylated tau (p-tau) and related isoforms were consistently identified as correlating with systemic AD pathology, including Braak staging. Experimental and clinical studies revealed early retinal changes, such as ganglion cell degeneration and blood-retina barrier breakdown, that preceded cognitive decline. Diagnostic advancements, including curcumin fluorescence imaging, ferritin nanocages, and hyperspectral imaging, demonstrated enhanced precision and feasibility for detecting retinal tau and Aβ in vivo and postmortem. These findings suggest that retinal tau serves as a robust biomarker for AD.

CONCLUSIONS: Retinal tau pathology represents a powerful diagnostic tool, providing non-invasive access to early AD pathology. By integrating molecular insights with advanced imaging modalities, retinal biomarkers could enable earlier diagnosis, therapeutic monitoring, and personalized treatment strategies. Future research should focus on longitudinal validation of retinal biomarkers across diverse populations.},
}

@article {pmid42877578,
year = {2026},
author = {Wang, R and Yang, Q and Cao, Z and Zhou, J and Tian, B and Wang, X and Zhang, X and Xiang, Q and Chen, G},
title = {From scavenger to victim: mechanism and treatment of microglial ferroptosis in white matter injury disease.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1859981},
pmid = {42877578},
issn = {1664-3224},
mesh = {*Ferroptosis ; Humans ; *Microglia/metabolism/pathology/immunology ; Animals ; *White Matter/pathology/metabolism/injuries/immunology ; Iron/metabolism ; *Leukoencephalopathies/metabolism/pathology ; Lipid Peroxidation ; Myelin Sheath/metabolism ; },
abstract = {Failure of myelin repair is a shared pathological feature of white matter injury (WMI)-associated diseases, including Alzheimer's disease (AD), vascular dementia (VaD), and multiple sclerosis (MS), but the underlying mechanisms remain incompletely understood. Microglia, the resident innate immune cells of the central nervous system (CNS), contribute to white matter homeostasis by clearing myelin debris and supporting remyelination. Within the iron- and lipid-rich white matter microenvironment, sustained uptake of myelin and oligodendroglial debris may impose phagocytic and metabolic stress on microglia, thereby increasing their susceptibility to ferroptosis, an iron-dependent form of regulated cell death driven by membrane phospholipid peroxidation. This susceptibility is regulated by interconnected mechanisms involving ferritinophagy-associated iron dysregulation, ACSL4/NOX2/15-LOX-related lipid peroxidation, and impaired endogenous ferroptosis-defense systems. Microglial responses are also heterogeneous: disease-associated, demyelination-associated, white matter-associated, lipid-droplet-accumulating, and degenerative microglial programs represent partially overlapping and context-dependent states rather than a proven linear trajectory. In susceptible microglial subsets, ferroptosis or ferroptosis-associated dysfunction may impair debris clearance and trophic support while promoting oxidized lipid accumulation and inflammatory signaling, thereby limiting remyelination. This review summarizes current evidence on the molecular mechanisms, multicellular interactions, microglial states, disease contexts, and therapeutic strategies associated with microglial ferroptosis in WMI. We further propose a functional therapeutic-window framework based on phagocytic competence, iron-lipid handling capacity, antioxidant reserve, and evidence of ferroptotic injury, and discuss major challenges in clinical translation. Overall, current evidence supports microglial ferroptosis as a context-dependent contributor to myelin repair failure rather than a universal determinant.},
}

*Ferroptosis
Humans
*Microglia/metabolism/pathology/immunology
Animals
*White Matter/pathology/metabolism/injuries/immunology
Iron/metabolism
*Leukoencephalopathies/metabolism/pathology
Lipid Peroxidation
Myelin Sheath/metabolism

@article {pmid42877708,
year = {2026},
author = {Li, S and Yu, Y and Cunanan, V and Masaki, K and Ross, GW},
title = {Lifestyle, APOE ε4, amyloid burden, and race/ethnicity differences in cognition, mood, and anxiety among cognitively unimpaired older adults.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {4},
pages = {e70494},
pmid = {42877708},
issn = {2352-8729},
abstract = {INTRODUCTION: We assessed whether lifestyle, race/ethnicity, and apolipoprotein E gene (APOE) ε4 were associated with cognition or mood/anxiety.

METHODS: This secondary cohort analysis used data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) Study and the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) cohort. Cognitively unimpaired adults aged 65 to 85 years (n = 1705) reported baseline lifestyle behaviors (summed as healthy lifestyle index [HLI]). APOE ε4 carrier status and amyloid positron emission tomography were assessed at baseline, while cognitive, anxiety, and depressive outcomes were assessed longitudinally. Associations were tested using mixed-effects models.

RESULTS: Among Non-Hispanic White participants, higher HLI was associated with fewer depressive symptoms, sufficient sleep was associated with smaller ε4-related increases in anxiety, and excessive alcohol use amplified ε4-related cognitive decline. Among participants from other racial/ethnic groups, walking and higher HLI were associated with more favorable anxiety/depression trajectories.

DISCUSSION: Adequate sleep, limited alcohol, walking, and no smoking may support emotional and cognitive health.},
}

@article {pmid42341744,
year = {2026},
author = {Marth, L and Lund, A and Höglinger, G and Levin, J},
title = {[Dementia with Lewy bodies].},
journal = {Fortschritte der Neurologie-Psychiatrie},
volume = {94},
number = {9},
pages = {340-350},
pmid = {42341744},
issn = {1439-3522},
support = {EXC 2145 SyNergy ID 390857198//Deutsche Forschungsgemeinschaft/ ; },
mesh = {Humans ; *Lewy Body Disease/diagnosis/therapy/psychology/pathology/epidemiology ; alpha-Synuclein/metabolism ; Biomarkers ; Lewy Bodies/pathology ; },
abstract = {Dementia with Lewy bodies (DLB) is the second most common neurodegenerative type of dementia after Alzheimer’s disease and belongs to the atypical parkinsonian syndromes. It is characterized by cognitive fluctuations, visual hallucinations, REM sleep behavior disorder, and parkinsonism. Typically, cognitive impairment appears before or within one year after the onset of motor symptoms (“one-year rule”). Neuropathologically, DLB is an α-synucleinopathy with neuronal Lewy bodies, often accompanied by copathologies. Diagnosis is based on clinical McKeith criteria and often supported by imaging biomarkers. Treatment is mainly symptomatic. Disease-modifying therapies are not yet available but are being investigated in clinical trials. The development of biologically defined diagnostic criteria and molecular biomarkers is crucial for future therapeutic studies.},
}

Humans
*Lewy Body Disease/diagnosis/therapy/psychology/pathology/epidemiology
alpha-Synuclein/metabolism
Biomarkers
Lewy Bodies/pathology

@article {pmid42870221,
year = {2026},
author = {Lee, GY and Han, SN},
title = {The Receptor for Advanced Glycation End Products: Regulation and Implications in Metabolic Diseases.},
journal = {IUBMB life},
volume = {78},
number = {10},
pages = {e70137},
doi = {10.1002/iub.70137},
pmid = {42870221},
issn = {1521-6551},
support = {NRF-RS-2024-00353119//National Research Foundation (NRF) of Korea/ ; },
mesh = {Humans ; *Receptor for Advanced Glycation End Products/metabolism/genetics ; Signal Transduction ; Animals ; Glycation End Products, Advanced/metabolism ; *Metabolic Diseases/metabolism ; Alzheimer Disease/metabolism ; },
abstract = {Receptor for advanced glycation end-products (RAGE) was originally identified as a receptor for advanced glycation end-products; however, it can also bind a broader range of damage-associated molecular patterns, including S100 proteins, high mobility group box 1, and amyloid-β. Ligand-induced RAGE activation promotes receptor oligomerization and recruitment of diaphanous-related formin-1, which activates several intracellular cascades, leading to the production of inflammatory mediators and reactive oxygen species. RAGE expression is upregulated in disease-associated tissues, including adipose tissue in diabetes and microglia and neurons in Alzheimer's disease, and the mechanisms by which RAGE activation contributes to pathogenesis are disease-specific. The review summarizes the expression and activation of RAGE, and the potential mechanisms through which RAGE contributes to disease pathogenesis. We further discuss current and emerging strategies for modulating RAGE signaling and highlight their therapeutic potential in the prevention and treatment of RAGE-associated diseases.},
}

Humans
*Receptor for Advanced Glycation End Products/metabolism/genetics
Signal Transduction
Animals
Glycation End Products, Advanced/metabolism
*Metabolic Diseases/metabolism
Alzheimer Disease/metabolism

@article {pmid42870413,
year = {2026},
author = {Saengsomsuan, N and Sangkakit, L},
title = {Low-Volume Superior Trunk and Superficial Cervical Plexus Block With Sedation as the Sole Regional Anesthetic for Proximal Humerus Fracture Fixation in a Patient With Alzheimer Disease.},
journal = {The American journal of case reports},
volume = {27},
number = {},
pages = {e954296},
doi = {10.12659/AJCR.954296},
pmid = {42870413},
issn = {1941-5923},
mesh = {Humans ; Female ; Aged ; *Cervical Plexus Block/methods ; *Fracture Fixation, Internal ; *Alzheimer Disease/complications ; *Shoulder Fractures/surgery/complications ; Bupivacaine/administration & dosage ; Hypnotics and Sedatives ; Geriatric Anesthesia ; Anesthetics, Local/administration & dosage ; },
abstract = {BACKGROUND Proximal humerus open reduction and internal fixation (ORIF) is usually performed under interscalene brachial plexus block (ISB) or general anesthesia (GA). ISB causes ipsilateral phrenic nerve paresis in nearly all patients, and GA may raise the risk of postoperative neurocognitive disorders in elderly patients with cognitive impairment. We report the feasibility of a low-volume regional technique, used as the sole regional anesthetic with sedation, in a patient in whom GA avoidance was desirable. CASE REPORT A 68-year-old woman (American Society of Anesthesiologists physical status II) with Alzheimer's disease underwent ORIF of a closed right proximal humerus fracture via a deltopectoral approach under superior trunk block (STB) with 5 mL of 0.5% bupivacaine, combined with superficial cervical plexus block (SCPB) with 3 mL of 0.5% bupivacaine, totaling 8 mL, with propofol and dexmedetomidine sedation. Surgery lasted 174 minutes without intraoperative rescue analgesia. Heart rate ranged from 48 to 68 beats/min during dexmedetomidine infusion without anticholinergic treatment, and oxygen saturation remained at 100% with spontaneous ventilation preserved. The block provided analgesia for about 12 hours, with pain score 1/10 at rest at 24 hours, and satisfaction 10/10. No clinically evident respiratory compromise, Horner's syndrome, or postoperative delirium was observed, although diaphragmatic and cognitive function were not formally assessed. The patient was discharged on postoperative day 2. CONCLUSIONS In this single patient, low-volume STB combined with SCPB was a feasible sole regional anesthetic technique, supported by sedation, for proximal humerus ORIF, completed without conversion to GA or clinically evident respiratory compromise. Respiratory and cognitive outcomes were clinically uneventful but not formally measured; broader utility remains to be established.},
}

Humans
Female
Aged
*Cervical Plexus Block/methods
*Fracture Fixation, Internal
*Alzheimer Disease/complications
*Shoulder Fractures/surgery/complications
Bupivacaine/administration & dosage
Hypnotics and Sedatives
Geriatric Anesthesia
Anesthetics, Local/administration & dosage

@article {pmid42870580,
year = {2026},
author = {Wang, S and Hu, T and He, M and Qin, M and Hu, Y and Zhao, L and Qin, Z},
title = {Cross-tissue graph attention networks for semi-supervised gene expression prediction.},
journal = {Briefings in bioinformatics},
volume = {27},
number = {5},
pages = {},
pmid = {42870580},
issn = {1477-4054},
mesh = {Graph Neural Networks ; Humans ; *Alzheimer Disease/genetics/metabolism ; *Gene Expression Profiling/methods ; Algorithms ; *Gene Expression ; *Computational Biology/methods ; Brain/metabolism ; },
abstract = {High-throughput biotechnologies have significantly advanced precision medicine by enabling the exploitation of global gene expression patterns to enhance our understanding of disease etiology, progression, and treatment options. However, the tissue-specific nature of gene expression presents a challenge, particularly for less accessible tissues such as the brain, underscoring the need for computational methods to accurately impute gene expression in these critical but hard-to-reach tissues. While several attempts to impute gene expression in tissue-specific contexts have shown promising results, their reliance on regression analysis faces limitations due to the inability to capture complex, nonlinear relationships in gene expression patterns. In contrast, modern machine learning techniques, particularly graph neural networks, have demonstrated superior performance by efficiently modeling the intricate interactions among genes across different tissues. Therefore, we introduce gene expression imputation with graph attention networks (gemGAT), a novel approach leveraging GATs to enhance gene expression prediction across different tissues. gemGAT distinguishes itself by predicting the expression of all genes simultaneously, utilizing the full spectrum of genomic data to account for gene coexpressions and nonlinear relationships. Validated through extensive experiments with Genotype-Tissue Expression data and a case study from the Alzheimer's Disease Neuroimaging Initiative, gemGAT demonstrates superior performance over existing methods by efficiently capturing nonlinear gene coexpressions. This advancement underscores gemGAT's potential to significantly contribute to precision medicine, showcasing its utility in advancing our understanding of gene expression in less accessible tissues.},
}

Graph Neural Networks
Humans
*Alzheimer Disease/genetics/metabolism
*Gene Expression Profiling/methods
Algorithms
*Gene Expression
*Computational Biology/methods
Brain/metabolism

@article {pmid42870749,
year = {2026},
author = {Vossberg, DAF and Rolfes, V and Fangerau, H and Haupt, M},
title = {Medical Decision-Making Capacity in Early-Stage Alzheimer Patients: Comparison With Healthy Controls and Benefit of Assistive Information.},
journal = {Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society},
volume = {26},
number = {6},
pages = {e70227},
pmid = {42870749},
issn = {1479-8301},
support = {2020-1061//Alzheimer Society of Germany (Deutsche Alzheimer Gesellschaft)/ ; },
mesh = {Humans ; *Alzheimer Disease/psychology/diagnosis ; Female ; Male ; *Decision Making ; Aged ; *Mental Competency/psychology ; *Informed Consent/psychology ; Aged, 80 and over ; Case-Control Studies ; Neuropsychological Tests ; *Audiovisual Aids ; },
abstract = {BACKGROUND: Early-stage Alzheimer Disease (AD) may lead to restricted decision-making capacity and without standardized instruments, there is great variability in determining patients' ability to give consent. This study aimed to assess decision-making capacity of AD patients in comparison to a healthy control group and investigated the usefulness of visual aids.

METHODS: A group of 30 ad patients and 30 healthy controls were compared using the MacArthur Competence Assessment Tool for Treatment (MacCAT-T). Additionally, we implemented a modified version of the MacCAT-T with visual aids.

RESULTS: Results revealed a significant difference in the MacCAT-T domain of Understanding between the AD and control group after adjustment for age, sex, and education. No significant differences were found for Appreciation, Reasoning, or Expression of Choice. Adding visual aids led to no significant improvements.

CONCLUSIONS: Standardized assessments can be valuable tools for determining the decision-making capacity of patients with early-stage AD. The efficacy of visual aids should be further investigated.},
}

Humans
*Alzheimer Disease/psychology/diagnosis
Female
Male
*Decision Making
Aged
*Mental Competency/psychology
*Informed Consent/psychology
Aged, 80 and over
Case-Control Studies
Neuropsychological Tests
*Audiovisual Aids

@article {pmid42872064,
year = {2026},
author = {Cai, W and Yi, Y and Zeng, R and Yin, Y and Zhao, J and Zhang, J and Fu, G and Xu, H},
title = {HMGB1 functional plasticity in neurodegenerative diseases and its translational implications.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1928641},
pmid = {42872064},
issn = {1664-3224},
mesh = {Humans ; *HMGB1 Protein/metabolism/genetics ; *Neurodegenerative Diseases/metabolism ; Animals ; Translational Research, Biomedical ; Signal Transduction ; Alarmins/metabolism ; Biomarkers ; },
abstract = {High mobility group box 1 (HMGB1) is a chromatin-associated protein that can be redistributed and released during cellular stress, when it acts as an extracellular alarmin within the broader family of damage-associated molecular patterns (DAMPs). Its functions depend on subcellular localization, redox and post-translational modification state, cellular source, mode of release, and molecular partners. This critical narrative review examines how these variables shape HMGB1 biology in Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), spinocerebellar ataxias (SCAs), frontotemporal dementia (FTD), and related disorders, and considers their implications for biomarker and therapeutic development. Intracellular HMGB1 contributes to chromatin organization, DNA repair, mitochondrial genome maintenance, and proteostasis. After redistribution and release, extracellular HMGB1 signals through receptors including the receptor for advanced glycation end products (RAGE) and Toll-like receptor 4 (TLR4), interacts with disease-associated proteins, and links proteostatic stress with glial activation, neuronal dysfunction, and blood-brain barrier impairment. Across disease models, two recurrent patterns emerge: loss or sequestration of intracellular HMGB1 in models of polyglutamine disorders, including HD and SCAs, and extracellular HMGB1 signaling as a progression-associated inflammatory amplifier in AD, PD, and ALS models. Central-peripheral inflammatory communication and cell-specific HMGB1 release further shape these responses. Clinical studies have associated total HMGB1 or anti-HMGB1 autoantibodies with clinical features, but current assays do not resolve redox form, cellular source, or biological activity. Most therapeutic studies remain preclinical, while available human intervention studies involve drugs with multiple molecular actions. Clinical translation requires redox-resolved and standardized assays, longitudinal human sampling, compartment- and cell-specific causal studies, and interventions with documented target engagement, central nervous system exposure, and long-term safety. HMGB1 is best understood as a context-dependent mediator rather than a uniformly pathogenic factor or a single treatment target.},
}

Humans
*HMGB1 Protein/metabolism/genetics
*Neurodegenerative Diseases/metabolism
Animals
Translational Research, Biomedical
Signal Transduction
Alarmins/metabolism
Biomarkers

@article {pmid42872207,
year = {2026},
author = {Wang, M and VanderVeen, B and Xu, ZA and Xu, Y and Mintzer, J and Murphy, A and Zhang, Q and Xu, P},
title = {Reverse the progression of Alzheimer's disease through Nano-ERASER-based adult neuroregeneration.},
journal = {Cell biomaterials},
volume = {},
number = {},
pages = {},
pmid = {42872207},
issn = {3050-5623},
support = {P30 GM154632/GM/NIGMS NIH HHS/United States ; R01 AG054839/AG/NIA NIH HHS/United States ; R01 CA263747/CA/NCI NIH HHS/United States ; R41 AG087769/AG/NIA NIH HHS/United States ; },
abstract = {Alzheimer's disease (AD) remains irreversible largely because the adult brain cannot replace lost neurons. Here, we present a Nano-ERASER-based Trim-Away system (TN-PTBP1) that enables adult neuroregeneration in the AD brain, offering a new strategy to counteract AD progression. TN-PTBP1 penetrates the blood-brain barrier, delivers anti-PTBP1 antibodies into astrocytes, and triggers rapid TRIM21-mediated PTBP1 degradation. This non-genomic protein depletion induces astrocyte-to-neuron conversion, generates functional neurons in vitro and in human brain organoids, and restores hippocampal neurogenesis in AD mice. Importantly, TN-PTBP1 treatment significantly improves cognition, learning, and memory, demonstrating true functional reversal of AD-associated deficits. By resolving the long-standing controversy surrounding PTBP1 reprogramming and establishing a translational biomaterials-based platform for in situ neuronal regeneration, this work introduces a transformative therapeutic paradigm aimed not only at slowing AD but at rebuilding the neuronal circuitry it destroys.},
}

@article {pmid42872450,
year = {2026},
author = {Kang, K},
title = {Bilateral Lower Extremity Edema During Donepezil Treatment: A Case Report.},
journal = {Current drug safety},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115748863527540260928113823},
pmid = {42872450},
issn = {2212-3911},
abstract = {Introduction/ Background: Acute bilateral lower-extremity edema is uncommon and often results from medication side effects, acute heart failure, nephrotic syndrome, or bilateral deep vein thrombosis. Drugs such as dihydropyridine calcium channel blockers, corticosteroids, thiazolidinediones, and nonsteroidal anti-inflammatory agents are known to cause edema. Donepezil, a widely used acetylcholinesterase inhibitor for Alzheimer's disease, has not been previously linked to leg edema. Recognizing rare adverse reactions is essential for patient safety, as edema may indicate serious conditions. Case Presentation: A 75-year-old woman with Alzheimer's disease developed bilateral pitting lower leg edema six months after starting treatment with donepezil. She had no history of cardiac, renal, hepatic, or venous diseases. Laboratory tests, electrocardiography, chest X-ray, and computed tomography venogram were normal, except for mild anemia and a slightly reduced estimated glomerular filtration rate. The edema resolved three weeks after discontinuation and did not recur after the administration of rivastigmine. Conclusion: The temporal association and resolution upon drug cessation suggest a probable association. Possible mechanisms may include cholinergic-induced vasodilation, which increases capillary permeability.},
}

@article {pmid42872643,
year = {2026},
author = {Patel, R and Sinha, S and Shukla, KS and Singh, B and Ved, A and Kumar, A and Yadav, N and Singh, V},
title = {Therapeutic Significance of Natural vs. Synthetic Coumarins in Alzheimer's Disease.},
journal = {Mini reviews in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113895575482030261005073306},
pmid = {42872643},
issn = {1875-5607},
abstract = {INTRODUCTION/OBJECTIVE: Coumarin, a naturally occurring aromatic compound bearing a benzopyrone scaffold, represents a versatile motif in synthetic drug design. Recent therapeutic developments have highlighted its potential as a privileged pharmacophore for neurodegenerative disorders (NDs), with particular efficacy targeting Alzheimer's disease (AD). This study presents a critical, comparative review of natural versus synthetic coumarins, evaluating their neuroprotective mechanisms across various preclinical, non-transgenic models of sporadic Alzheimer's disease (sAD).

METHODS: Natural coumarins (e.g., umbelliferone, esculetin, and scopoletin) exert potent antioxidant, anti-inflammatory, and moderate enzyme-inhibitory activities, particularly against acetylcholinesterase (AChE) and β-amyloid (Aβ) aggregation. These phytochemicals attenuate neurodegeneration by modulating oxidative stress and neuroinflammatory pathways across various cellular and rodent models, including 5xFAD mice, as well as streptozotocin (STZ)-and scopolamine (SCOP)- induced Alzheimer's disease (AD) rat models. However, their clinical utility remains constrained by poor bioavailability and modest potency. To address these limitations, synthetic coumarin derivatives, including coumarin-pyrrolidine, coumarin-triazole, coumarin-chalcone, and coumarin-donepezil hybrids, as well as hydroxycoumarins, have been developed. These heterocyclic hybrid architectures exhibit superior therapeutic potency, enhanced blood-brain barrier (BBB) permeability, and synergistic inhibition of core pathological targets, including AChE activity and Aβ aggregation.

RESULT: Both in vivo preclinical models and in silico docking simulations substantiate the neuroprotective capacity of coumarin-based frameworks, demonstrating substantial cognitive rescue, restored synaptic plasticity, and favorable safety margins. Moving beyond the baseline safety of naturally derived coumarins, structural optimization and hybrid design strategies serve as a compelling framework for developing potent, multi-target therapeutics for neurodegenerative diseases.

DISCUSSION: According to the review, Alzheimer's disease treatment is shifting from natural coumarins to multi-target-directed ligands (MTDLs) because natural compounds, such as esculetin, scopoletin, and daphnetin, are often limited by narrow target specificity and lower potency than synthetic coumarin derivatives.

CONCLUSION: Herein, the authors review the biological activities of natural coumarins and their synthetic analogs as potential therapeutics for Alzheimer's disease (AD). This study systematically compared and evaluated the therapeutic efficacy and structural scaffold variations of both natural and synthetic derivatives. To support their translational potential, this study also summarizes current ADMET profiles and pharmacokinetic evaluations, which represent key prerequisites for clinical advancement.},
}

@article {pmid42872646,
year = {2026},
author = {Budak Savaş, A and Yeşilyurt, F and Hacimuftuoglu, A},
title = {From Hypothesis to Clinical Validation: A Bibliometric Mapping of Immunotherapy for Neurodegenerative Proteinopathies (2000-2025).},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273531307261012100737},
pmid = {42872646},
issn = {1996-3181},
abstract = {INTRODUCTION/OBJECTIVE: For twenty-five years, despite persistent challenges, the field of neurodegenerative disease has remained committed to a single hypothesis: targeting the immune system directly against misfolded proteins accumulating in the brain. Today, this approach has produced a clinical counterpart, with three monoclonal antibodies now approved, although the field is still progressing toward clinical validation. However, the research lines, countries, institutions, and journals through which this point was reached, and how far that validation has actually progressed, have remained largely unexamined.

METHODS: This study analyzes 9,863 articles published between 2000 and 2025 using bibliometric methods to map the field's intellectual structure, productivity patterns, and the thematic evolution shaped around four turning points.

RESULTS: The findings reveal a nonlinear trajectory. Annual output rose from a steady pace in the early 2000s to a sudden surge after 2019, exceeding 900 publications per year. Research output is heavily concentrated in the United States, while impact is concentrated among a small number of core journals and prolific authors. Only 47 journals account for one-third of the literature, and roughly four out of five authors have contributed only a single publication to the field. While the amyloid hypothesis continues to rest on strong genetic foundations, which protein species is actually neurotoxic, soluble oligomers or deposited plaques, remains an open question, and this keeps alive the debate over what clinical trials are truly measuring. The safety of approved drugs, particularly ARIA-related imaging abnormalities, and the challenge of delivering treatment across the blood-brain barrier stand out as fronts the field has yet to overcome.

DISCUSSION: Perhaps the most notable signal is that this accumulated progress now appears to be extending beyond Alzheimer's disease: thematic patterns suggest the same immunotherapeutic logic is beginning to extend toward Parkinson's disease and other proteinopathies.

CONCLUSION: The study presents, within a single framework, the critical periods the field has passed through, who has led this journey, and which questions remain unanswered.},
}

@article {pmid42872652,
year = {2026},
author = {Watson, D and Neam, MG and Stafford, M and Bouchard, C and Ranney, V and Werner, S},
title = {Transitioning from Clinical Trial to Clinical Practice for Long-Term Lecanemab Treatment in Early Alzheimer's Disease: Perspectives from a Cohort Study from the Alzheimer's Research and Treatment Center.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050525938260923072703},
pmid = {42872652},
issn = {1875-5828},
abstract = {INTRODUCTION/BACKGROUND: Lecanemab, an anti-amyloid monoclonal antibody, significantly reduces amyloid markers and slows clinical decline in early Alzheimer's disease (AD) clinical trials. We assessed our single-center experience with lecanemab, including evaluating efficacy and safety data as well as patient-reported outcomes of individuals from our single center treated with intravenous or subcutaneous lecanemab.

MATERIALS AND METHODS: We conducted a single-center, nested cohort study of early AD subjects on lecanemab (intravenous or subcutaneous) at our center. Participants had been initiated on lecanemab therapy as part of lecanemab Study 201 or Clarity AD, and then continued lecanemab treatment in our center. Data collection included patient demographic characteristics, efficacy (eg, CDR-SB), safety, and patient-reported outcomes from surveys.

RESULTS: At our center, 136 people were randomized to receive either lecanemab or placebo in either lecanemab Study 201 (lecanemab:53; placebo:16) or Clarity AD (lecanemab:37; placebo:30). Patients receiving lecanemab were more likely to have higher rates of stable or improved disease across efficacy assessments relative to placebo. There were no new long-term safety signals, and the most common adverse events for lecanemab patients were infusion-related reactions (36.2%), ARIA-H (25.9%), and ARIA-E (13.8%). Survey responses demonstrated high satisfaction with the subcutaneous lecanemab administration, including with treatment satisfaction (97%) and convenience (97%). All patients preferred subcutaneous over IV dosing, citing quickness, ease, and comfort.

DISCUSSION: Our single-center experience with long-term lecanemab treatment was similar to that observed in clinical trials.

CONCLUSION: The subcutaneous lecanemab formulation was highly preferred by patients and care partners, with feedback highlighting reduced treatment burden and strong acceptability.},
}

@article {pmid42872679,
year = {2026},
author = {Li, M and Lv, S and Cui, L and Fang, S},
title = {Tetrachloro-1,4-benzoquinone Exerts Neurotoxicity through Neuroinflammation and the TLR4 Signaling Pathway, which is a Risk Factor for Alzheimer's Disease: An Integrated Network and Mendelian Randomization Analysis.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050502048260925094031},
pmid = {42872679},
issn = {1875-5828},
abstract = {INTRODUCTION: Research has found that the disinfection byproduct Tetrachloro-1,4- Benzoquinone (TCBQ) in drinking water increases the risk of Alzheimer's Disease (AD). However, the mechanism by which TCBQ increases the risk of AD remains unclear.

METHODS: This study employs a comprehensive approach that includes network toxicology (PPI network, hub genes, KEGG analysis), Mendelian randomization, computational simulations (molecular docking and dynamics), and cellular experiments to systematically elucidate the neurotoxic mechanisms of TCBQ.

RESULTS: Key findings indicate that TCBQ induces neurotoxicity by activating the Toll-like receptor signaling pathway, AD, and the apoptosis pathway. All ligand-receptor docking energies are recorded at ≤ -1.8 kcal/mol, suggesting that TCBQ demonstrates a stable interaction with the targets. Molecular simulations confirm that TCBQ tightly binds to targets such as Caspase3 and TLR4. Mendelian randomization found that XDH, FABP3, IMPDH1, ACBD7, and CASP3 are common targets and play a potential role in AD. Immunofluorescence experiments revealed that APP expression increased after TCBQ treatment. Cellular experiments verified that TCBQ significantly upregulates the expression of inflammation- and apoptosis-related proteins, including IL-1B, MyD88, NFκB, TLR4, Cleaved-Caspase3, and Cyt C, leading to neuronal cell death. Notably, the TLR4 inhibitor effectively reversed the expression of these proteins and alleviated cell death.

DISCUSSION: The discussion indicates that TCBQ induces neurotoxicity by activating the TLR4 pathway and apoptotic signals, and Caspase3 is a potential co-target. TLR4 inhibitors can reverse protein alterations and cell death, suggesting that intervention in this pathway may alleviate TCBQrelated nerve damage.

CONCLUSION: Our research provides a theoretical basis for the clinical assessment of potential neurotoxicity risks in populations exposed to TCBQ.},
}

@article {pmid42873344,
year = {2026},
author = {Lee, M and Lee, S and Kim, JH and Oh, MS},
title = {Rheum undulatum Linné Exerts Neuroprotective Effects Against Aβ Oligomer-Induced Neuronal Damage by Modulating p53-Mediated Signaling.},
journal = {Neurochemical research},
volume = {51},
number = {5},
pages = {},
pmid = {42873344},
issn = {1573-6903},
support = {RS-2023-KH138733//Korea Health Industry Development Institute/ ; RS-2023-KH138733//Korea Health Industry Development Institute/ ; RS-2023-KH138733//Korea Health Industry Development Institute/ ; RS-2023-KH138733//Korea Health Industry Development Institute/ ; },
mesh = {Animals ; *Amyloid beta-Peptides/toxicity ; *Neuroprotective Agents/pharmacology/therapeutic use/isolation & purification ; *Signal Transduction/drug effects/physiology ; *Tumor Suppressor Protein p53/metabolism ; *Rheum/chemistry ; *Neurons/drug effects/metabolism ; Mice ; Male ; Peptide Fragments/toxicity ; Mice, Inbred C57BL ; *Plant Extracts/pharmacology/therapeutic use ; Hippocampus/drug effects/metabolism ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and synaptic dysfunction. Accumulating evidence indicates that β-amyloid oligomers (AβO), the most neurotoxic form of β-amyloid, play a critical role in the pathogenesis of AD by inducing synaptic loss, neuronal death, and neuroinflammation. Therefore, targeting AβO-driven pathological processes through multi-target therapeutic strategies represents a promising approach to treating AD. This study aimed to investigate the neuroprotective effects of Rheum undulatum Linné rhizome (RUL) and the underlying mechanisms of its action against AβO-induced neurotoxicity using integrated in vitro, in vivo, and in silico approaches. RUL treatment protected HT22 and N2a neuronal cells from AβO-induced neurotoxicity and reduced extracellular AβO levels. In AβO-injected mice, oral administration of RUL alleviated memory impairment, preserved synaptic integrity, as evidenced by increased PSD95 and SYP expression, and suppressed microglial and astrocytic activation, as indicated by reduced Iba-1 and GFAP immunoreactivity in the hippocampus. Mechanistically, systems-level network analysis identified p53-related signaling as a central regulatory axis in the AD-associated pathway. These network-level insights were experimentally validated by demonstrating that RUL suppressed p53 phosphorylation, increased the BCL2/Bax ratio, inhibited caspase-3 activation, and reduced pro-inflammatory cytokines, including TNF-α and IL-1β, in the hippocampus. Collectively, these findings demonstrate that RUL exerts neuroprotective effects by preserving synaptic integrity and concurrently suppressing apoptotic and neuroinflammatory pathways through the network-level modulation of AβO-driven pathology, supporting its potential as a multi-target therapeutic candidate for AD.},
}

Animals
*Amyloid beta-Peptides/toxicity
*Neuroprotective Agents/pharmacology/therapeutic use/isolation & purification
*Signal Transduction/drug effects/physiology
*Tumor Suppressor Protein p53/metabolism
*Rheum/chemistry
*Neurons/drug effects/metabolism
Mice
Male
Peptide Fragments/toxicity
Mice, Inbred C57BL
*Plant Extracts/pharmacology/therapeutic use
Hippocampus/drug effects/metabolism

@article {pmid42873357,
year = {2026},
author = {Gündoğdu, AA and Özkan, NG and Adapınar, DÖ},
title = {The small giant actor in the pathogenesis of neurodegenerative diseases: Microtubules.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {42873357},
issn = {1573-7365},
mesh = {Humans ; *Microtubules/metabolism/pathology ; *Neurodegenerative Diseases/metabolism/pathology ; Animals ; tau Proteins/metabolism ; Axonal Transport/physiology ; },
abstract = {Neurodegenerative diseases are a clinically and pathologically diverse group of disorders characterized by progressive neuronal dysfunction, synaptic impairment, and neuronal loss. Although research has traditionally focused on disease-associated protein misfolding and aggregation, increasing evidence implicates abnormalities of cytoskeletal organization and intracellular transport in several neurodegenerative conditions. Microtubules contribute to neuronal polarity, axonal and dendritic transport, organelle distribution, and synaptic maintenance. These functions are regulated in part by tubulin isotypes, post-translational modifications collectively described as the tubulin code, microtubule-associated proteins, and molecular motors. This narrative review examines evidence linking alterations in these processes with Alzheimer's disease, Parkinson's disease, frontotemporal dementia, Huntington's disease, amyotrophic lateral sclerosis, and prion disease. We summarize proposed interactions among microtubule instability, impaired axonal transport, mitochondrial dysfunction, and disease-associated proteins, including tau, α-synuclein, mutant huntingtin, TDP-43, and prion protein. Evidence connecting tau pathology with microtubule dysfunction is comparatively well established in Alzheimer's disease and MAPT-related tauopathies, whereas findings in other disorders are more heterogeneous and are frequently derived from cellular or animal models. We also discuss emerging experimental approaches, candidate biomarkers, and investigational microtubule-directed treatments. However, no tubulin-specific biomarker or microtubule-targeted disease-modifying treatment discussed in this review has yet been clinically validated. Overall, microtubule dysfunction may represent one component of broader, disease-specific pathological networks rather than a universal primary cause of neurodegeneration. Further longitudinal and clinical studies are needed to determine whether microtubule-related alterations act as causes, consequences, or modifiers of disease progression.},
}

Humans
*Microtubules/metabolism/pathology
*Neurodegenerative Diseases/metabolism/pathology
Animals
tau Proteins/metabolism
Axonal Transport/physiology

@article {pmid42874179,
year = {2026},
author = {Qu, L and Wang, Y and Ren, L and Zhang, C and Guo, Z and Zhang, L and Pang, X and Sha, S},
title = {Advancing early detection of Alzheimer's disease: from established biomarkers to future innovations.},
journal = {International immunopharmacology},
volume = {190},
number = {},
pages = {117537},
doi = {10.1016/j.intimp.2026.117537},
pmid = {42874179},
issn = {1878-1705},
abstract = {Alzheimer's disease (AD) is a major form of dementia, imposes an escalating global burden on public health and social care. Pathological changes in AD occur years before clinical symptoms, defining a prolonged preclinical phase. Currently, there is no effective treatment exist for late-stage AD, making early diagnosis and intervention indispensable, in which biomarkers play a pivotal role. While cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers improved AD diagnostic accuracy, their clinical application is limited by invasiveness, high costs. Advances in ultrasensitive immunoassay technologies has rendered peripheral blood biomarkers easily accessible, cost-effective, minimally invasive, and suitable for continuous monitoring, offering noval opportunities for AD screening, diagnosis and progression tracking. Additionally, non-invasive body fluids including saliva, urine and tears are being explored as potential biomarkers. Artificial intelligence (AI)-driven multimodal fusion, integrated with large-scale multimodal computing frameworks, significantly improve the accuracy of early AD diagnosis. Recent studies have identified a series of promising synaptic and neuronal biomarkers, such as neurofilament light chain (NFL), neurogranin (Ng), β-secretase 1 (BACE1) and synaptosomal-associated protein 25 (SNAP-25). Inflammatory mediators and genetic factors also contribute to AD pathological evaluation. This review systematically characterizes biomarker profiles of emerging non-invasive carriers (saliva, urine and tears). It further synthesizes cohort-derived quantitative diagnostic metrics (AUC, sensitivity, specificity) of multimodal AD biomarkers and conducts head-to-head comparison to clarify their respective strengths and translational limitations, aiming to provide evidence-based insights for optimizing early AD screening and diagnostic strategies.},
}

@article {pmid42874425,
year = {2026},
author = {Le Scouarnec, L and Bouteloup, V and Grasset, L and Planche, V and Chêne, G and Dufouil, C and , },
title = {Estimating the eligible population for amyloid-targeting monoclonal antibody therapy in memory clinics: Application to lecanemab in France.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {10},
pages = {100683},
doi = {10.1016/j.tjpad.2026.100683},
pmid = {42874425},
issn = {2426-0266},
abstract = {Lecanemab was the first amyloid-targeting monoclonal antibody approved by the European Commission for treating patients with mild cognitive impairment (MCI) and mild dementia due to Alzheimer's disease (AD). While this marketing authorization led to heterogeneous situations across European countries, France declined reimbursement, citing limited clinical benefit and concerns about the healthcare system's capacity to implement this new care pathway. This capacity depends directly on the number of eligible patients, yet robust estimates remain limited and highly variable across studies. Our objective was therefore to estimate the population eligible for lecanemab in France. Using transportability methods based on inverse odds of selection weighting, we articulated the nationwide consultation data from the French National Alzheimer Database (BNA) with the deeply phenotyped MEMENTO clinical cohort. Eligibility for lecanemab followed the French appropriate use recommendations: 1) clinical eligibility (age 50-90 years, MCI with common AD phenotype or mild AD dementia, MMSE ≥22), 2) biological eligibility (amyloid confirmation determined sequentially using plasma p-tau217, cerebrospinal fluid biomarkers and amyloid-PET), 3) absence of contraindications (APOEε4 homozygosity, anticoagulant use, MRI risk markers for ARIA). Among patients consulting French memory clinics, 19.5% met clinical eligibility criteria. Of these, 73.0% (95%CI: 67.6-77.9) were amyloid-positive, and 49.7% (95%CI: 44.0-55.5) remained eligible after applying safety criteria. Overall, 9.7% (95%CI: 8.6-10.8) of patients consulting memory clinics were estimated to be eligible for lecanemab, representing approximately 18,200 individuals nationally (annual average, 2022-2024). These results inform healthcare planning for disease-modifying therapy implementation in France and comparable countries.},
}

@article {pmid42874747,
year = {2026},
author = {Xiao, X and Gao, F and Xie, J and Lu, Y and Lv, K and Mo, H and Chen, J and Liu, J and Meng, Q and Guan, Y and Chen, Q},
title = {Fucosylated Chondroitin Sulfate Modulates Microglia-Associated Responses and Reduces Aβ Burden with ERK1/2-Related Signaling Changes.},
journal = {Neurochemistry international},
volume = {},
number = {},
pages = {106278},
doi = {10.1016/j.neuint.2026.106278},
pmid = {42874747},
issn = {1872-9754},
abstract = {INTRODUCTION: Fucosylated chondroitin sulfate (FCS) is a sulfated polysaccharide derived from the marine organism Apostichopus japonicus. This study aimed to investigate its neuroprotective potential, specifically focusing on microglial modulation and ERK1/2 signaling, in Alzheimer's disease (AD) models.

METHODS: An integrated in vitro and in vivo approach was employed. In vitro, Aβ42-stimulated BV2 microglia were treated with FCS, and the broad protein kinase C activator TPA was used as a pharmacological perturbation to examine whether the FCS-associated ERK1/2 signaling changes were reversible. Cytokine levels, microglial phenotype markers (CD86, CD206, iNOS, Arg-1), Aβ handling, and MAPK pathway proteins (p-ERK1/2, p38, JNK) were analyzed. In vivo, 5xFAD transgenic mice received intraperitoneal FCS for 28 days. Aβ plaque burden, soluble/insoluble Aβ levels, cognitive performance (Morris water maze, Y-maze), cortical Iba1-positive cell counts, activation state (Iba1[+]CD86[+], Iba1[+]CD206[+]), and expression of p-ERK1/2, iNOS, and Arg-1 were assessed.

RESULTS: In vitro, FCS attenuated Aβ42-induced pro-inflammatory responses (reduced IL-6, TNF-α; increased IL-10), modulated phenotype (decreased CD86/iNOS; increased CD206/Arg-1), and increased the cell-associated Aβ fraction while reducing supernatant Aβ. FCS reduced Aβ42-associated ERK1/2 phosphorylation and the nuclear-to-cytoplasmic p-ERK1/2 fluorescence signal ratio, and these changes were partially attenuated by TPA. In vivo, FCS treatment reduced cerebral Aβ burden, improved spatial and working memory, decreased the number and proportion of cortical Iba1[+]CD86[+] microglia, and increased the Iba1[+]CD206[+] subset. Cortical p-ERK1/2/total ERK1/2 and iNOS expression were downregulated, while Arg-1 was upregulated.

CONCLUSION: FCS reduced Aβ-related pathological burden, improved selected behavioral outcomes, and modulated microglia-associated inflammatory and phenotype-related readouts in AD models. These effects were accompanied by ERK1/2-related signaling changes, supporting a pathway-associated interpretation rather than definitive proof of ERK1/2 causality in vivo.},
}

@article {pmid42875627,
year = {2026},
author = {Hwang, J and Delman, BN and Naasan, G},
title = {Intracranial metastasis as a mimic of amyloid-related imaging abnormalities.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {11},
pages = {},
pmid = {42875627},
issn = {1590-3478},
mesh = {Humans ; Female ; *Brain Neoplasms/secondary/diagnostic imaging ; Aged ; Diagnosis, Differential ; *Thyroid Neoplasms/pathology/diagnostic imaging ; Carcinoma, Papillary/diagnostic imaging ; *Alzheimer Disease/diagnostic imaging/drug therapy ; Brain Edema/diagnostic imaging ; Magnetic Resonance Imaging ; Brain/diagnostic imaging ; Amyloid/metabolism ; },
abstract = {This report describes a 79-year-old woman with biomarker-confirmed Alzheimer's disease who developed progressive vasogenic edema initially interpreted as amyloid-related imaging abnormalities (ARIA) with edema during lecanemab therapy, but was ultimately found to have multifocal intracranial metastases from recurrent papillary thyroid carcinoma. The serial neuroimaging highlights the diagnostic challenge of distinguishing ARIA from alternative causes of vasogenic edema in the era of anti-amyloid monoclonal antibody treatment. In addition, this case raises an important and underexplored question regarding whether anti-amyloid therapies may alter blood-brain barrier integrity in a manner that could influence metastatic spread in susceptible patients.},
}

Humans
Female
*Brain Neoplasms/secondary/diagnostic imaging
Aged
Diagnosis, Differential
*Thyroid Neoplasms/pathology/diagnostic imaging
Carcinoma, Papillary/diagnostic imaging
*Alzheimer Disease/diagnostic imaging/drug therapy
Brain Edema/diagnostic imaging
Magnetic Resonance Imaging
Brain/diagnostic imaging
Amyloid/metabolism

@article {pmid42875646,
year = {2026},
author = {Kumar, A},
title = {Synergistic approaches to Alzheimer's disease: exploring the combined efficacy of phytoconstituents and conventional drugs.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {42875646},
issn = {1568-5608},
abstract = {BACKGROUND: Cognitive functions deteriorate with Alzheimer's disease (AD), a kind of degenerative disease. Problems with memory, interpersonal interactions, problem-solving, and other cognitive functions that limit a person's ability to do daily tasks are the hallmarks of dementia. This condition affects about 50 million individuals globally. Traditional therapies for AD, like galantamine, donepezil, and memantine, only offer symptomatic alleviation through glutamatergic regulation and cholinergic augmentation, making AD a significant worldwide health concern.

OBJECTIVE: This review assesses the possibility of improving the effectiveness of therapy by combining significant phytoconstituents with traditional AD therapies.

METHODS: A complete literature review was carried out using peer-reviewed publications, experimental investigations, and review papers published from 2010 to 2025. The primary objective of the investigation was to study the interaction between phytoconstituents and conventional therapy in the treatment of Alzheimer's disease.

RESULT: Our outcomes demonstrate the powerful multi-target adjuvant properties of curcumin, resveratrol, quercetin, berberine, and luteolin. In particular, Berberine and Quercetin considerably reduce neuroinflammation and oxidative stress through the Nrf2/HO-1 and NF-κB pathways, whereas Curcumin and resveratrol enhance the anti-amyloidogenic effects of conventional medications. Additionally, luteolin exhibits a special capacity to regulate tau hyperphosphorylation, which enhances memantine's stabilising neurotransmitter actions.

DISCUSSION: The primary objective of therapy has shifted from symptomatic relief to disease modification by the synergy between phytoconstituent and conventional drugs. These combinations preserve the structural integrity of the cholinergic synapse by concurrently mitigating oxidative stress and amyloid toxicity.

CONCLUSION: A possible paradigm shift towards holistic neuroprotection is represented by the incorporation of these five essential phytoconstituents into traditional AD regimens. To ensure clinical translatability, future research must now focus on nanoformulations that can overcome the limited bioavailability of substances like curcumin. These methods may improve treatment effectiveness, lessen adverse effects, and reduce the chance of resistance, providing a more thorough method of handling the complexities of AD.},
}

@article {pmid42875809,
year = {2026},
author = {Liu, ZP and Lee, D and Tan, Z and Wu, A and Mei, L and Xiong, WC},
title = {Levetiracetam restores GABAergic function and network homeostasis following Vps35 deficiency in excitatory neurons.},
journal = {Translational neurodegeneration},
volume = {15},
number = {1},
pages = {},
pmid = {42875809},
issn = {2047-9158},
support = {AG045781/NH/NIH HHS/United States ; },
mesh = {Animals ; Mice ; *Levetiracetam/pharmacology ; *Vesicular Transport Proteins/deficiency ; *Homeostasis/drug effects/physiology ; Mice, Knockout ; *Neurons/drug effects/metabolism ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) and related dementias (ADRDs) remain incurable, partly due to their complex and poorly understood pathogenic mechanisms. Loss of vacuolar protein sorting-associated protein 35 (VPS35), a core component of the retromer complex, has been implicated in AD and ADRDs. While Vps35 deficiency is known to increase amyloidogenesis by regulating its cargo proteins, such as APP and BACE1, the precise mechanism by which VPS35 dysfunction leads to cognitive impairment remains elusive. While neuronal VPS35 regulates trafficking and functions of multiple synaptic membrane proteins, such as postsynaptic glutamatergic and GABAnergic receptors and pre-synaptic vesicle protein SV2A, and Levetiracetam (LEV), an antiepileptic drug that improves cognition, interacts with the SV2A, exactly how LEV enhances cognition is still a matter of debate.

METHODS: Given the abundant expression of VPS35 in pyramidal excitatory neurons, we generated a conditional knockout mouse model with Vps35 deletion from postnatal glutamatergic excitatory neurons (Vps35[CaMKIIα]) and characterized its phenotypes using a combination of behavioral assessments, and electrophysiological, biochemical, and immunohiotological analyses in the hippocampal CA1 region. A targeted pharmacological screen was conducted to evaluate the therapeutic potential of LEV.

RESULTS: Vps35 deletion did not disrupt the gross brain development but led to progressive cognitive decline beginning at three months of age. Electrophysiological analyses revealed earlier-onset hippocampal CA1 hyperexcitability, marked by depolarized resting membrane potentials and reduced Kir2.1 expression. However, restoring Kir2.1 to suppress hyperexcitability failed to rescue cognitive deficits. Instead, cognitive impairment was associated with weakened GABAergic transmission and disruption of the excitatory/inhibitory balance in the Schaffer collateral-CA1 circuit. Notably, LEV treatment diminished these deficits in mutant mice. Intriguingly, LEV increased the levels of retromer component, VPS26A, and multiple pre- and postsynaptic GABAergic proteins, in addition to SV2A, all of which were reduced in Vps35-deficient CA1 neurons.

CONCLUSIONS: These findings identify VPS35 in excitatory neurons as a critical factor for inhibitory synapse maintenance and network homeostasis. This study also highlights LEV as a potential therapeutic strategy for ADRDs through the preservation of GABAergic synapses.},
}

Animals
Mice
*Levetiracetam/pharmacology
*Vesicular Transport Proteins/deficiency
*Homeostasis/drug effects/physiology
Mice, Knockout
*Neurons/drug effects/metabolism

@article {pmid42876862,
year = {2026},
author = {Jiang, Y and Lin, H and Hong, B and Yue, L},
title = {Donanemab-associated clinical improvement in Alzheimer's disease presenting predominantly with neuropsychiatric symptoms: A case report.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261478025},
pmid = {42876862},
issn = {2542-4823},
abstract = {Late-life depression may mask Alzheimer's disease (AD). We report a 78-year-old man with treatment-refractory depressive and anxiety symptoms accompanied by paroxysmal somatic attacks, unresponsive to psychotropic treatment and modified electroconvulsive therapy. Ultimately, biomarker evaluation confirmed AD pathology, and donanemab was initiated. Follow-up amyloid positron emission tomography demonstrated marked amyloid clearance, particularly in the frontal lobe, accompanied by concurrent improvement in depressive symptoms, cognition, and reduced somatic attacks. This case suggests that anti-amyloid therapy may benefit AD patients presenting with refractory neuropsychiatric symptoms, potentially related to frontal amyloid clearance, underscoring the importance of AD screening in resistant late-life depression.},
}

@article {pmid42876885,
year = {2026},
author = {Hazan, J and Salemme, S and Liu, KY and Howard, R},
title = {How should the results of Alzheimer's disease treatment trials be communicated to colleagues, patients, and families?.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {4},
pages = {e70330},
pmid = {42876885},
issn = {2352-8737},
abstract = {The approval of amyloid-lowering therapies for Alzheimer's disease (AD) has increased the importance of clearly and precisely communicating complex clinical trial findings to patients, caregivers, clinicians, and the wider public. Because the clinical relevance of the modest treatment effects observed on cognitive and functional rating scales, which served as primary trial outcome measures, is uncertain and difficult to interpret, these effects have been translated into alternative quantitative interpretations, such as relative slowing of decline and time-saved estimates, and supplemented with qualitative descriptions and patient or caregiver testimonials. In this perspective, we examine the advantages and limitations of these approaches, with a particular focus on time-saved approaches, and discuss the assumptions required to move beyond reliance on directly observed primary outcome data from clinical trials. We argue that alternative methods of communicating treatment effects may improve accessibility but introduce additional uncertainty and may lead patients and clinicians to overestimate the size of benefit because they will not appreciate some of the assumptions on which these methods are based. Clear and accurate communication of treatment benefits, risks, limitations, and evidential uncertainty is essential to support informed decision making and maintain public trust in AD research and treatment.},
}

@article {pmid42876904,
year = {2026},
author = {Tagane, Y and Nakamori, M and Ishida, M and Tsuchigauchi, S and Sugimoto, T and Yamazaki, Y and Maruyama, H},
title = {Steroid-responsive inflammatory leptomeningeal encephalitis temporally associated with lecanemab therapy: A case report.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261483284},
pmid = {42876904},
issn = {2542-4823},
abstract = {Lecanemab is an anti-amyloid-β monoclonal antibody used for the treatment of early Alzheimer's disease. Herein, we report a 46-year-old woman who developed headache, fever, disorientation, and impaired consciousness 10 months after starting lecanemab. Magnetic resonance imaging revealed a small focal subcortical fluid-attenuated inversion recovery hyperintense lesion and bilateral occipital leptomeningeal enhancement without detectable hemorrhagic findings on T2*-weighted gradient-recalled echo imaging. Cerebrospinal fluid revealed mononuclear pleocytosis and markedly elevated interleukin-6. Infectious studies and neuronal surface antibodies were negative. High-dose corticosteroid therapy led to rapid clinical improvement. These findings support a diagnosis of steroid-responsive inflammatory leptomeningeal encephalitis temporally associated with lecanemab.},
}

@article {pmid42876920,
year = {2026},
author = {Nakashima, S and Sato, K and Niimi, Y and Ihara, R and Iwata, A and Nemoto, K and Arai, T and Higashi, S and Igarashi, A and Kasuga, K and Akiyama, H and Awata, S and Ikeda, M and Toda, T and Iwatsubo, T},
title = {Identifying facility-level and infrastructure-level bottlenecks in Japan's lecanemab rollout through an online survey of dementia specialists.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261470054},
pmid = {42876920},
issn = {2542-4823},
abstract = {BACKGROUND: The approval of lecanemab has created new operational demands for Alzheimer's disease care. Japan's nationwide rollout under universal health insurance offers an opportunity to identify real-world bottlenecks in treatment delivery.

OBJECTIVE: To identify facility-level and infrastructure-level factors associated with wait time to initial lecanemab infusion and treated patient volume among dementia specialists in Japan.

METHODS: We performed a secondary analysis of an anonymous online survey of 296 dementia specialists certified to prescribe lecanemab in Japan approximately one year after approval. We examined associations between physician/facility characteristics, diagnostic and infusion resources, perceived implementation barriers, and two delivery metrics: wait time from first consultation to first infusion and number of treated patients per respondent. Bayesian accelerated failure-time and zero-truncated Poisson mixed-effects models were used.

RESULTS: Approximately 80% of respondents reported average wait times of 3 months or less, whereas the median treated caseload was modest at 5 patients per physician. Perceived mismatch between treatment capacity and demand was associated with longer wait time (time ratio 1.323, 95% credible interval 1.045-1.682). Cerebrospinal fluid (CSF)-dominant amyloid-testing strategies tended to be associated with smaller caseloads, while in-house CSF testing and APOE testing were associated with larger caseloads. High-volume centers reported constrained outpatient infusion space. Lack of reimbursement for infusion-related tasks and APOE testing were perceived as major system-level barriers.

CONCLUSIONS: Japan's rollout may be constrained by some bottlenecks in diagnostics, infusion infrastructure, and uncompensated tasks. Appropriate policy interventions might help secure equitable access to the treatment.},
}

@article {pmid42877253,
year = {2026},
author = {Starr, EG and Dhaliwal, J and McLatchey, MG and Young, NP and Lai, B},
title = {Neurons on the rocks: A case of alcohol use and early onset Alzheimer's disease.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261459404},
pmid = {42877253},
issn = {2542-4823},
abstract = {A 46-year-old female was admitted to the hospital for confusion, cognitive decline, and hallucinations with alcohol withdrawal. Her history was notable for Alcohol use disorder (AUD) and family history of Alzheimer's disease (AD). Comprehensive workup was unrevealing for metabolic encephalopathy, infection, or nutritional deficiencies. Phosphatidyl ethanol level was 1181, indicating severe alcohol misuse. Phospho-Tau 217 testing raised suspicion of AD and FDG-PET scan confirmed patterns consistent with early onset AD. AUD can precipitate earlier or more severe onset of AD. Phospho-Tau 217 can be a useful screening marker to identify people at risk of AD to prompt intensive treatment.},
}

@article {pmid42877265,
year = {2026},
author = {Yajima, R and Ishiguro, T and Michikawa, M and Naruse, S},
title = {Caregiver burden, not patient cognitive impairment, predicts adherence to donepezil transdermal patch in Alzheimer's disease: A retrospective real-world study.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261468306},
pmid = {42877265},
issn = {2542-4823},
abstract = {BACKGROUND: The donepezil transdermal patch is a useful option for Alzheimer's disease (AD) patients with poor oral adherence. However, treatment discontinuation due to skin irritation or management difficulties remains a clinical challenge.

OBJECTIVE: To identify predictive factors for the successful continuation of the donepezil transdermal patch in a real-world setting.

METHODS: A retrospective review included 26 AD patients newly prescribed or switched to the donepezil patch at a dementia center. Patients were divided into continuation (n = 15) and discontinuation (n = 11) groups based on a 12-week cutoff. We evaluated baseline demographics, Mini-Mental State Examination (MMSE), Clinical Dementia Rating-Sum of Boxes (CDR-SB), Alzheimer's Disease Assessment Scale-Cognitive Subscale for Activities of Daily Living (ADL-Cog), and caregiver burden using the 8-item Zarit Burden Interview (Zarit-8). Multivariate logistic regression identified risk factors for discontinuation.

RESULTS: Univariate analysis showed no significant differences between groups in age (p = 0.855), MMSE (p = 0.677), CDR-SB (p = 0.762), and ADL-Cog (p = 0.826). Although the mean Zarit-8 score was higher in the discontinuation group (14.00 ± 10.70 versus 7.86 ± 5.55, p = 0.171), this lacked statistical significance. However, multivariate regression revealed a higher Zarit-8 score was a significant independent predictor of discontinuation after adjusting for age (p = 0.038, OR = 1.134).

CONCLUSIONS: Caregiver burden, rather than patient cognitive function or impairment in activities of daily living, significantly predicts discontinuation of the transdermal patch. To the best of our knowledge, no previous studies have utilized the Zarit burden scale as a clinical predictor of pharmacological adherence. Assessing caregiver reserve before introduction is crucial for maintaining adherence.},
}

@article {pmid42877307,
year = {2026},
author = {Imamura, J},
title = {Pre-pilot study: Reactivating brain waste clearance via vasopressin fragment-A novel approach to Alzheimer's disease therapy.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261449497},
pmid = {42877307},
issn = {2542-4823},
abstract = {BACKGROUND: Impaired clearance of amyloid-β (Aβ) and other metabolic waste products has been implicated in Alzheimer's disease (AD). Arginine vasopressin (AVP) fragments have been associated with memory-related effects and may influence glymphatic-related pathways.

OBJECTIVE: This pre-pilot exploratory study investigated the potential effects of an AVP (4-9) fragment analog on Aβ-related biomarkers and cognitive function.

METHODS: Seven participants (three healthy adults and four individuals with AD) received intranasal administration of an AVP (4-9) fragment analog for two weeks at a daily dose of 60 ng. Aβ-related burden was assessed using blood-based Composite Biomarker (CB) values reported to correlate with amyloid PET findings. Cognitive function in AD participants was evaluated using the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog).

RESULTS: At baseline, CB values were 5- to 20-fold higher in individuals with AD than in healthy adults. Following treatment, mean CB values in the AD group decreased by 36%, with comparable relative reductions observed across groups. ADAS-Cog scores improved by a mean of 8.1 points over two weeks. No adverse events were observed.

CONCLUSIONS: AVP (4-9) fragments may influence cognitive processes and glymphatic-related pathways. These findings should be interpreted cautiously given the small sample size and open-label design but may provide a basis for future controlled investigations.},
}

@article {pmid42877345,
year = {2026},
author = {Xin, J and Zhang, H and Cai, S and Li, J and Dou, G and Estrada, BB and Walker, C and Storm, R and Chen, X},
title = {Diagnostic journey, biomarker testing, treatment, and care partner burden in patients with mild cognitive impairment and Alzheimer's disease dementia in China: A real-world survey.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261447853},
pmid = {42877345},
issn = {2542-4823},
abstract = {BACKGROUND: The prevalence of Alzheimer's disease (AD) is rising in China. Although disease-modifying treatments are available, their efficacy is mostly seen in the early stage. Timely and accurate diagnosis is crucial for AD management.

OBJECTIVE: This study aimed to describe the diagnostic trajectory, current treatments, and care burden for mild cognitive impairment (MCI)/AD in China.

METHODS: Data were derived from the Adelphi Real World Dementia Disease Specific Programme™, a cross-sectional survey of neurologists, patients with MCI/AD dementia and their care partners, conducted in China from February-May 2024. Patient characteristics, diagnoses, treatments, and care were reported by neurologists and supplemented by self-reports from patients and care partners.

RESULTS: Overall, 93 neurologists reported on 774 patients. Of patients with a Mini-Mental State Examination (MMSE) score at the time of survey (n = 699), mean (standard deviation) age was 69.3 (8.2) years, 49.6% (n = 347) female and most had MCI/mild AD (MMSE 20-28) at survey (52.5%, n = 367). Over one-third of patients presented with moderate to severe disease at initial consultation (34.7%, n = 203) and at diagnosis (36.2%, n = 265). Biomarker testing was infrequently used in diagnosis, with cerebrospinal fluid being the most used (11.2%, n = 81) and physician-reported challenges including cost, patient reluctance, and availability. Most patients received only non-professional care primarily from a partner/spouse and/or children, who spent up to 47.0 (45.8) hours per week caring.

CONCLUSIONS: Challenges in early and biomarker-based diagnosis were identified and care partners continued to experience a substantial burden. Continued efforts are needed to ensure the healthcare system's preparedness for the AD epidemic.},
}

@article {pmid42863362,
year = {2026},
author = {Zhou, Z},
title = {Uncovering the mechanism of gastrodin in treating Alzheimer's disease through bioinformatics, machine learning, and virtual gene knockout technology.},
journal = {Computational biology and chemistry},
volume = {126},
number = {Pt 2},
pages = {109464},
doi = {10.1016/j.compbiolchem.2026.109464},
pmid = {42863362},
issn = {1476-928X},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline. Gastrodin is a natural compound with neuroprotective activity; however, the precise molecular mechanisms underlying its therapeutic effects on human AD remain unclear. This study employed bioinformatics approaches to systematically elucidate the therapeutic mechanisms of gastrodin in AD. Pharmacokinetic analysis showed that gastrodin exhibited favorable drug-like properties (bioavailability score: 0.55; LogP: -0.85) and an acceptable overall toxicity profile, although predicted nephrotoxicity (0.71) and ototoxicity (0.908) scores suggest potential safety concerns warranting further investigation. Next, differentially expressed genes (DEGs) associated with AD were screened from GEO datasets, yielding 13 core targets that overlapped with gastrodin-responsive genes. Functional enrichment analysis indicated significant enrichment of these targets in signaling pathways closely related to neuroinflammation and cell survival, including the Ras-proximate 1 (Rap1), Ras, mitogen-activated protein kinase (MAPK), and phosphatidylinositol 3-kinase-protein kinase B (PI3K-Akt) pathways. The Ridge model achieved AUCs of 0.898 in the training set and 0.859 in the GSE37263 cohort, but showed modest generalizability in the GSE138260 cohort (AUC = 0.684), highlighting the heterogeneity of external datasets. Further single-cell transcriptomic analysis revealed specific upregulation of insulin-like growth factor 1 receptor (IGF1R) in brain endothelial cells of AD patients. Virtual gene knockout simulations demonstrated that IGF1R knockout substantially disrupted core networks associated with endothelial functions and neurovascular homeostasis, including focal adhesion and calcium signaling pathways. Finally, molecular docking and molecular dynamics (MD) simulations revealed stable binding conformations of gastrodin to EGFR and MET, while the gastrodin-IGF1R complex exhibited a more dynamic binding behavior with conformational flexibility, suggesting an induced-fit binding mechanism. MM/PBSA calculations revealed favorable enthalpic contributions (ΔH = -17.43, -13.63, and -10.41 kcal/mol for EGFR, IGF1R, and MET, respectively) for gastrodin-target binding. In conclusion, this study suggests that gastrodin exerts multi-target effects via coordinated regulation of multiple signaling pathways. Notably, gastrodin targets IGF1R in brain endothelial cells, modulating focal adhesion/calcium signaling networks, thus providing a novel mechanistic hypothesis for AD treatment by restoring neurovascular unit homeostasis.},
}

@article {pmid42863691,
year = {2026},
author = {Urano, Y and Maeda, W and Noguchi, N},
title = {Inhibition of glycan sialylation reduces amyloid-β secretion via suppression of amyloid-β exocytosis.},
journal = {Biochimie},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.biochi.2026.10.016},
pmid = {42863691},
issn = {1638-6183},
abstract = {Among nutrient-sensitive regulatory mechanisms, protein glycosylation is a key post-translational modification that links metabolism to protein function. Amyloid-β (Aβ) peptides play a crucial role in the pathogenesis of Alzheimer's disease (AD). Because excessive accumulation of Aβ is believed to drive AD progression, approaches that reduce Aβ production and secretion remain of considerable therapeutic interest. Accumulating evidence suggests that protein glycosylation influences the processing and trafficking of amyloid-β precursor protein (APP) and other proteins involved in Aβ metabolism. However, while N-linked protein glycosylation has been shown to affect Aβ production, the specific contribution of protein terminal glycan sialylation remains incompletely understood. In this study, we investigated the effects of inhibiting glycan sialylation on Aβ production using CHO cells stably expressing human APP. Treatment with the sialyltransferase inhibitor P-3Fax-Neu5Ac (P-3Fax) significantly reduced extracellular Aβ levels, while intracellular Aβ levels were increased. Importantly, P-3Fax treatment did not alter β-secretase- or γ-secretase-mediated cleavage of their substrates, indicating that changes in secretase activity do not account for the reduction in extracellular Aβ. In addition, P-3Fax treatment markedly reduced plasma membrane levels of lysosome-associated membrane protein 1 (LAMP1), consistent with impaired lysosomal exocytosis. Taken together, these results indicate that inhibition of sialylation by P-3Fax reduces extracellular Aβ levels independently of secretase activity, potentially through impaired lysosomal exocytotic pathways. Our findings identify glycan sialylation as a key regulatory factor in Aβ trafficking and provide new insight into the cellular mechanisms controlling Aβ homeostasis.},
}

@article {pmid42863694,
year = {2026},
author = {Tanahashi, M and Kozuka, A and Sasakawa, N and Niikura, T},
title = {Humanin attenuates neuronal cellular senescence and preserves neurotransmitter release in differentiated PC12 cells.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2026.10.017},
pmid = {42863694},
issn = {1873-7544},
abstract = {Cellular senescence, characterized as a permanent arrest of cell proliferation, is triggered by various types of stress. Senescent cells are identified by markers, including senescence-associated β-galactosidase (SA-β-gal) activity and the secretion of senescence-associated secretory phenotype (SASP) factors. These senescent phenotypes have been observed in neurons, suggesting that cellular senescence may contribute to the pathogenesis of neurodegenerative diseases. Humanin (HN), an endogenous short peptide, mitigates Alzheimer's disease-associated pathologies, including amyloid β-induced neuronal cell death. Overexpression of HN extends the lifespan of nematodes, suggesting a potential anti-aging role for this peptide. Here, we first investigated the effect of HN on cellular senescence in mouse primary cortical neurons. Chronic treatment with HNG, a highly potent HN derivative, attenuated prolonged culture-induced senescence. To further determine whether this anti-senescent effect is associated with preserved exocytotic function, we employed a glutamate-induced senescence model in neuronal-differentiated PC12 cells. In this system, HNG mitigated changes in senescence-associated markers, including increases in SA-β-gal activity, Ki67 expression, and SASP factor expression. In addition, acetylcholine-induced dopamine release was reduced in senescent PC12 cells, whereas chronic HN treatment sustained the expression levels of synapsin 1 and synaptophysin and attenuated the senescence-associated decrease in neurotransmitter release. These findings suggest that HN suppresses senescence and sustains exocytosis activity in neuronal cells, supporting an anti-aging function of HN at the cellular level.},
}

@article {pmid42863728,
year = {2026},
author = {Li, Y and Tang, ZL and Liu, FW and Chen, M and Chang, SQ and Ding, FM and Bian, QL and Pan, JP and Qiu, ZC and Kong, MW and Li, Y and Chen, JX},
title = {Si-Shen-San Attenuates Alzheimer's Disease Pathology and Cognitive Deficits Through Multi-Target Regulation of Astrocyte Function and Synaptic Plasticity.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {122475},
doi = {10.1016/j.jep.2026.122475},
pmid = {42863728},
issn = {1872-7573},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder pathologically characterized by cognitive decline, amyloid-β (Aβ) deposition, tau hyperphosphorylation, synaptic dysfunction, and astrocyte dysregulation. The constituent herbs of the traditional Chinese medicine formula Si-Shen-San (SSS) have been used to ameliorate cognitive impairment. However, the comprehensive chemical profile, core bioactive constituents, and underlying mechanisms of action of SSS remain to be fully elucidated.

AIM OF THE STUDY: This study aims to systematically investigate the therapeutic potential of SSS against AD and to clarify its multi-faceted mechanisms of action, with a focus on astrocyte-mediated neuroprotection, synaptic repair, and modulation of core AD pathologies.

MATERIALS AND METHODS: Ultra-high performance liquid chromatography-quadrupole/time-of-flight mass spectrometry (UHPLC-Q/TOF-MS) was used to characterize the chemical constituents of SSS extract and SSS-containing serum. In vivo, 3×Tg-AD mice were orally administered SSS. And cognitive function, AD-related pathology, synaptic integrity, and astrocyte-associated molecular changes were evaluated using behavioral, histological, biochemical, ultrastructural, and electrophysiological approaches. In vitro, an astrocyte-conditioned medium paradigm was used to examine whether SSS-induced changes in astrocytes were associated with protection of HT22 neurons against glutamate-induced injury.

RESULTS: UHPLC-Q/TOF-MS tentatively annotated 525 and 318 compounds in the SSS extract and drug-containing serum. In 3×Tg-AD mice, SSS improved cognitive performance, reduced hippocampal 6E10- and ThS-positive Aβ-like immunoreactivity and tau phosphorylation at Thr231 and Ser404, and preserved synaptic structure and function. The reduction in tau phosphorylation was accompanied by changes in GSK-3β signaling. SSS treatment was also associated with reduced astrocyte reactivity, increased GLT-1 expression, and restoration of astrocyte-associated homeostatic markers. In vitro, conditioned medium derived from SSS-treated C8-D1A astrocytes alleviated glutamate-induced injury in HT22 neurons and was accompanied by activation of neuronal CREB-BDNF signaling.

CONCLUSION: SSS ameliorated cognitive deficits and multiple AD-related pathological alterations in 3×Tg-AD mice. These effects were associated with restoration of astrocyte-related homeostatic features, improved glutamate regulation, preservation of synaptic integrity, and activation of CREB-BDNF signaling. These findings provide an experimental foundation for SSS as a potential therapeutic strategy for AD and highlight astrocyte homeostasis as a promising target for future drug development.},
}

@article {pmid42865133,
year = {2026},
author = {Lv, Y and Shi, M and Zhao, Y and Yu, Y and Lv, J and Zhao, H},
title = {Context-dependent TREM2 signalling in myeloid cells: Molecular mechanisms and immunotherapeutic divergence in neurodegeneration and cancer.},
journal = {Clinical and translational medicine},
volume = {16},
number = {10},
pages = {e70863},
pmid = {42865133},
issn = {2001-1326},
support = {ZR2022QH372//Shandong Province Natural Science Foundation/ ; },
mesh = {Humans ; *Receptors, Immunologic/metabolism ; *Membrane Glycoproteins/metabolism ; *Signal Transduction ; *Myeloid Cells/metabolism/immunology ; *Neoplasms/therapy/immunology ; Animals ; *Immunotherapy/methods ; *Neurodegenerative Diseases/therapy/immunology ; },
abstract = {BACKGROUND: Triggering receptor expressed on myeloid cells 2 (TREM2) is a pivotal lipid-sensing receptor that governs the functional plasticity and metabolic fitness of mononuclear phagocytes, including microglia, osteoclasts, dendritic cells and tissue-resident macrophages. While originally identified as a genetic risk factor for Alzheimer's disease (AD), TREM2 functions as a context-dependent immunometabolic checkpoint rather than a uniform phenotypic driver, exerting divergent biological outputs dictated by distinct tissue microenvironments and ligand repertoires.

SUMMARY OF KEY CONTENTS: This review provides a comprehensive synthesis of TREM2 immunobiology, detailing how ligand engagement-including cell-surface phospholipids and apolipoprotein E (ApoE)-activates the DAP12/DAP10-SYK-PI3K-mTOR signalling axis. This coordinated intracellular cascade instructively drives myeloid adaptation towards metabolically competent disease-associated microglia (DAM) and lipid-associated macrophage (LAM) states, sustaining bioenergetics and debris clearance under pathological stress. Across neurodegenerative proteinopathies and acute cerebral ischemia, TREM2 signalling is predominantly neuroprotective by promoting aggregate compaction and mitigating secondary excitotoxicity, although chronic dysregulated activation may drive stage-dependent neuroinflammation. In peripheral inflammatory pathologies such as rheumatoid arthritis and sepsis, TREM2 fine-tunes macrophage efferocytosis and systemic metabolic thresholds. In oncology, TREM2 displays a complex, microenvironment-dependent divergence: in central nervous system malignancies such as glioblastoma (GBM), TREM2 exerts controversial, stage-dependent effects, spanning microglial tumour containment in early stages versus pro-tumoural myelin recycling and immunosuppression by monocyte-derived macrophages in post-treatment recurrence; conversely, in peripheral solid tumours, monocyte-derived TREM2+ tumour-associated macrophages (TAMs) predominantly orchestrate an immunosuppressive, nutrient-deprived niche that impairs cytotoxic T-cell function. Furthermore, we synthesise emerging paradigms along the bidirectional microbiome-gut-brain-tumour axis, elucidating how commensal and intra-tumoural microbial cues dynamically calibrate myeloid signalling tone and therapeutic susceptibility.

CONCLUSION: We address translation bottlenecks-including blood-brain barrier (BBB) shuttles, human trial scarcity and soluble TREM2 (sTREM2) biomarker harmonisation-outlining a biomarker-guided, context-tailored precision therapeutic framework for targeting the TREM2 axis.},
}

Humans
*Receptors, Immunologic/metabolism
*Membrane Glycoproteins/metabolism
*Signal Transduction
*Myeloid Cells/metabolism/immunology
*Neoplasms/therapy/immunology
Animals
*Immunotherapy/methods
*Neurodegenerative Diseases/therapy/immunology

@article {pmid42865340,
year = {2026},
author = {Kamonnat, C and Thongdechsri, S and Kraokaew, P and Niamnont, N and Sobhon, P and Meemon, K},
title = {Protective Role of Holothuria leucospilota Extract Against Amyloid-β Toxicity via Autophagy and Antioxidant Mechanisms in Caenorhabditis elegans Model.},
journal = {Oxidative medicine and cellular longevity},
volume = {2026},
number = {1},
pages = {e1471919},
pmid = {42865340},
issn = {1942-0994},
support = {//National Research Council of Thailand/ ; N42A660511//Mahidol University/ ; AN-KME-3-66-02//Central Instrument Facility (CIF)/ ; },
mesh = {Animals ; *Caenorhabditis elegans/drug effects/metabolism ; *Amyloid beta-Peptides/toxicity/metabolism ; *Autophagy/drug effects ; *Antioxidants/pharmacology ; *Holothuria/chemistry ; Oxidative Stress/drug effects ; Disease Models, Animal ; Reactive Oxygen Species/metabolism ; *Plant Extracts/pharmacology ; Caenorhabditis elegans Proteins/metabolism ; Alzheimer Disease/drug therapy ; Animals, Genetically Modified ; },
abstract = {Alzheimer's disease (AD) is a major global health challenge characterized by cognitive decline and neuronal degeneration driven by amyloid-β (Aβ) aggregation and oxidative stress. Given the limited efficacy and adverse effects of current pharmacological therapies, food-derived bioactive compounds have gained increasing attention as potential preventive strategies against neurodegenerative disorders. In this study, we investigated the neuroprotective effects of Holothuria leucospilota extracts using a transgenic Caenorhabditis elegans model of AD. Our results demonstrated that H. leucospilota hexane extract (HLHE) at 500 µg/mL significantly delayed Aβ-induced paralysis and improved chemotaxis behavior. Consistently, HLHE treatment reduced Aβ deposition and decreased both high- and low-molecular weights of Aβ oligomers, as determined by automated Western blot analysis. Additionally, HLHE also reduced reactive oxygen species (ROS) levels. Transcriptomic and RT-qPCR analyses revealed that HLHE enhanced autophagic activity through the upregulation of bec-1 (autophagy initiation) and lysosomal genes (cpr-1, cpr-2, and cpr-5). Furthermore, HLHE activated antioxidant defense pathways via the insulin/IGF-1 signaling (IIS) axis, specifically upregulating genes associated with SKN-1 pathway (pmk-1, skn-1, gst-4, and gst-10) and HSF-1 pathway (hsf-1, hsp-16.1, hsp-12.6, and mtl-1). HLHE also promoted nuclear localization of SKN-1 and increased expression of its downstream target gst-4. Chemical analysis revealed that HLHE contained arachidonic acid (21.12%) and other bioactive lipid compounds as major constituents, suggesting a synergistic role in promoting autophagy and antioxidant responses. Collectively, this study suggests that HLHE confers neuroprotection against Aβ-induced toxicity by activating autophagy and oxidative stress defense mechanisms, supporting its potential development as a food-derived preventive or therapeutic agent for AD.},
}

Animals
*Caenorhabditis elegans/drug effects/metabolism
*Amyloid beta-Peptides/toxicity/metabolism
*Autophagy/drug effects
*Antioxidants/pharmacology
*Holothuria/chemistry
Oxidative Stress/drug effects
Disease Models, Animal
Reactive Oxygen Species/metabolism
*Plant Extracts/pharmacology
Caenorhabditis elegans Proteins/metabolism
Alzheimer Disease/drug therapy
Animals, Genetically Modified

@article {pmid42865480,
year = {2026},
author = {Li, SY and Zhang, JX and Huang, LZ and Wu, HB and Ye, YB and Liu, A and Chen, J and Lai, S},
title = {Efficacy and safety of lecanemab monoclonal antibody in the treatment of mild to moderate Alzheimer's disease: a systematic review and meta-analysis.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1947129},
pmid = {42865480},
issn = {1663-9812},
abstract = {BACKGROUND: Lecanemab is a novel therapy for Alzheimer's disease (AD), but comprehensive evidence is lacking. This systematic review and meta-analysis evaluated the efficacy and safety in AD.

METHODS: Registered in PROSPERO (CRD420251146867). PubMed, Embase, Cochrane Library, Web of Science, and Scopus were searched for English-language RCTs. Efficacy and safety were evaluated using the risk difference with a Mantel-Haenszel fixed-effects model. Study quality and sensitivity were assessed using Cochrane risk-of-bias and leave-one-out methods. Primary outcomes: mean changes in Alzheimer's Disease Composite Score (ADCOMS), Clinical Dementia Rating Scale Sum of Boxes (CDR-SB), Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), and amyloid burden on positron emission tomography (PET). Secondary: adverse events including amyloid-related imaging abnormalities with edema (ARIA-E), ARIA with hemorrhage (ARIA-H), death, treatment-emergent adverse events (TEAEs), headache, dizziness, and urinary tract infection.

RESULTS: A total of five articles involving 8 clinical trials were included. Based on the fixed-effect model, lecanemab treatment significantly improved cognitive performance on ADCOMS (SMD -0.1999, 95% CI [-0.2831, -0.1167], I[2] = 0%, P < 0.00001), CDR-SB (SMD -0.1853, 95% CI [-0.2683, -0.1024], I[2] = 0%, P < 0.0001), ADAS-Cog (SMD -0.1821, 95% CI [-0.2670, -0.0973], I[2] = 0%, P < 0.0001) and amyloid burden on PET (SMD -1.1872, 95% CI [-2.2474, -0.1270], I[2] = 96%, P = 0.03). Sensitivity analysis indicated stability. However, lecanemab was associated with an increased risk of TEAEs (MH RR 1.0730, 95% Cl [1.0296, 1.1183], I[2] = 0%, P = 0.0008) and an increased risk of headache (MH RR 1.3617, 95% Cl [1.0243, 1.8103], I[2] = 0%, P = 0.03). Sensitivity analysis indicated that both results were stable. The lecanemab group showed no significant differences in the risks of death, dizziness, or urinary tract infection compared with the control group. In addition, the lecanemab group showed a significantly increased risk of ARIA-E (MH RR 5.9948, 95% CI [3.9047, 9.2037], I[2] = 86%, P < 0.00001) and ARIA-H (MH RR 1.7490, 95% CI [1.3896, 2.2014], I[2] = 41%, P < 0.00001). Sensitivity analyses confirmed the stability of the TEAE finding, while the headache result should be interpreted with caution due to the limited number of studies. After excluding Honig et al. (OLE) 2021 via leave-one-out, results became stable, likely due to its open-label design.

CONCLUSION: Lecanemab slowed cognitive decline versus placebo in mild-to-moderate AD by ADCOMS, CDR-SB, and ADAS-Cog. High heterogeneity in PET amyloid burden warrants future RCTs. Nevertheless, lecanemab was associated with an increased risk of TEAEs and headache.

https://www.crd.york.ac.uk/PROSPERO/view/CRD420251146867.},
}

@article {pmid42865621,
year = {2026},
author = {Tan, W and Han, X and Wang, X and Tang, M and Li, S and Liu, H and Zhang, J and Wang, J and Liu, G},
title = {Multimodal MRI to elucidate cross-organ coupling mechanisms of the heart-brain axis.},
journal = {Frontiers in cardiovascular medicine},
volume = {13},
number = {},
pages = {1914265},
pmid = {42865621},
issn = {2297-055X},
abstract = {Cardiovascular and cerebrovascular diseases (CCVDs) are leading causes of mortality and disability worldwide, and their development is closely linked to bidirectional interactions between the heart and the brain. The heart-brain axis, a systemic framework that integrates neural, humoral, and inflammatory pathways, provides an important theoretical basis for understanding heart-brain comorbidities. With continuous advances in magnetic resonance imaging(MRI), research in this field has progressively shifted from the traditional single-organ diagnostic model to cross-organ and system-oriented strategies for prevention and management. Centered on cardiac magnetic resonance (CMR) and brain MRI, and complemented by quantitative, diffusion, functional, ultra-high-field, and metabolic imaging techniques, multimodal MRI has become a powerful tool for comprehensively characterizing myocardial remodeling, alterations in brain networks, and their coupling relationships. These techniques have been widely applied in studies of representative heart-brain comorbidities, including cardiac dysfunction associated with acute brain injury, cognitive impairment related to heart failure, and cardiovascular abnormalities associated with neurodegenerative diseases, such as Alzheimer's disease (AD). Such studies have not only revealed structural and functional alterations in the heart and brain but have also provided important insights into potential mechanisms, including autonomic imbalance, neuroendocrine activation, and inflammatory responses. However, current heart-brain axis research remains largely based on correlational analyses, whereas causal inference and characterization of dynamic mechanisms remain insufficient. In addition, significant challenges persist in multimodal data integration and clinical translation. Overall, MRI is driving heart-brain axis research from structural characterization toward mechanistic investigation. In the future, integrating imaging, physiological, and genetic information may enable early identification, risk stratification, and precision intervention for heart-brain comorbidities, thereby promoting a transition in medical practice from single-organ management to systemic prevention and treatment.},
}

@article {pmid42865677,
year = {2026},
author = {Wahbeh, H and Cooley, S and Chamberlin, SR and Brophy, T and Hameroff, S},
title = {Home-administered unfocused transcranial ultrasound in subjective cognitive decline and dementia: an open-label, uncontrolled feasibility pilot study.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1937897},
pmid = {42865677},
issn = {1663-4365},
abstract = {BACKGROUND: Memory and cognitive impairments remain disabling, with few effective treatments. Low-intensity transcranial ultrasound (TUS) is a non-invasive neuromodulation approach with a favorable safety profile and preliminary evidence of cognitive benefit, with one hypothesized but unproven mechanism involving microtubule resonance and reassembly.

OBJECTIVES: This open-label pilot study evaluated the safety and preliminary efficacy of the US Pro2000 unfocused ultrasound device in adults with memory or cognitive difficulties, a sample spanning subjective cognitive decline among self-administering participants to diagnosed dementia among caregiver-rated recipients, and described self-reported symptom trajectories.

METHODS: In a within-participant design, adults with self-reported cognitive impairment, or their caregivers, applied the device at the right temporal window for 5 min three times daily (target 15 min/day), in cycles of 3 weeks on and 1 week off. Outcomes (GAD-7, CESD-5, Inoue battery, and caregiver-rated MDS 3.0) and adverse events were collected online. Mixed-effects models with age and device-use covariates assessed change over time, with False Discovery Rate correction within aim.

RESULTS: Twenty-seven participants enrolled and 26 initiated treatment. Across 2,174 daily assessments, no serious or unanticipated adverse events occurred; only headache (15.4%) and transient jaw clenching (3.8%) were possibly related, and none caused discontinuation. Among self-administered participants, depression (CESD-5) declined significantly (p_FDR = 0.016) and five of eight monthly self-report symptoms improved, including memory, word-finding, and problem-solving (all p_FDR ≤ 0.040); anxiety trended downward, and the objective cognitive battery, near ceiling at baseline, did not change. Caregiver-rated outcomes were stable. Device use showed no dose response, and sensitivity analyses were consistent.

CONCLUSION: Home-based self-administered low-intensity TUS was well tolerated, with only mild transient events, although adverse-event ascertainment relied on unblinded self-report and relatedness judgments were made by unblinded investigators. Efficacy signals were confined to self-report, while objective cognition and caregiver ratings were unchanged. The uncontrolled design, small subgroups, and reliance on self-report preclude causal inference. These findings support the safety and feasibility of TUS and justify an adequately powered, double-blind, sham-controlled trial.},
}

@article {pmid42865929,
year = {2026},
author = {Ponomareva, EV and Selezneva, ND and Boksha, IS and Savushkina, OK and Prokhorova, TA and Tereshkina, EB and Zozulya, SA and Gavrilova, SI and Kolykhalov, IV},
title = {Pilot clinical study of Taxifolin Aqua effect in patients with amnestic mild cognitive impairment.},
journal = {Frontiers in psychiatry},
volume = {17},
number = {},
pages = {1814042},
pmid = {42865929},
issn = {1664-0640},
abstract = {Taxifolin (dihydroquercetin), a potent antioxidant flavonoid, shows promise for neurodegenerative conditions. Our pilot study aimed at evaluation the efficacy and safety of Taxifolin in patients with amnestic mild cognitive impairment (aMCI) and monitored a set of blood measures. Twenty-three patients (18 female; aged 53-87) received dihydroquercetin oral solution for 8 weeks with a 4-week follow-up period in an open-label study design. Thirteen patients with aMCI were monitored as controls. Outcomes were assessed using cognitive status (MMSE, MoCA, FCSRT-IR), neuropsychiatric symptoms' (NPI-Q, HDRS), and rater's impression (CGI) scales, along with blood measures monitoring (glutathione reductase (GR), glutamate dehydrogenase (GDH), and superoxide dismutase (SOD); plasma neutrophil elastase (NE), alpha-1-proteinase inhibitor (alpha-1PI)). Responder classification using composite Z-score changes was based on all clinical scales. Results: Eleven patients were classified as responders, showing significant MMSE and MoCA improvement (mean +2.73 points, p=0.001) sustained through 4-week follow-up. Non-responders and control group showed slight cognitive decline. Composite Z-score changes at the 4-week follow-up revealed differences between responders/non-responders (ANOVA F(2,20)=17.38, p=0.001); biomarker analysis revealed difference in NE/alpha-1PI ratio (p=0.034), SOD (p=0.023), and GR dynamics (p=0.022), which correlated negatively with clinical response (R=-0.547, p=0.007), and baseline GDH (p=0.049). Conclusion: Taxifolin treatment resulted in significant cognitive benefits in ~half of aMCI patients, with effects sustained for one month post-treatment. Biomarker changes reveal possible mechanisms involving oxidative stress modulation and inflammatory pathways. These findings support further controlled trials of Taxifolin in populations at risk of Alzheimer's disease.},
}

@article {pmid42866370,
year = {2026},
author = {Wang, T and Wang, L and Cao, J and Zhao, Y and He, Z and Lu, F},
title = {Remodeling of the brain immune microenvironment in Alzheimer's disease: interactions among microglia, astrocytes, complement, and the neurovascular unit.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1956600},
pmid = {42866370},
issn = {1664-3224},
mesh = {Humans ; *Alzheimer Disease/immunology/pathology/metabolism ; *Microglia/immunology/metabolism/pathology ; *Astrocytes/immunology/metabolism/pathology ; *Complement System Proteins/immunology/metabolism ; *Brain/immunology/pathology/metabolism/blood supply ; Animals ; *Cellular Microenvironment/immunology ; Amyloid beta-Peptides/metabolism ; },
abstract = {Alzheimer's disease is defined by amyloid-β deposition and tau pathology, yet comparable pathological burdens do not necessarily correspond to similar cognitive trajectories, regional patterns of injury, or treatment responses. This discordance suggests that the cellular and tissue microenvironment may materially shape disease progression. Genetic studies, single-cell and spatial omics, and human-derived models further indicate that microglia, astrocytes, the complement system, and the neurovascular unit undergo coordinated remodeling during the preclinical phase of AD and influence pathological spread, synaptic injury, and neurodegeneration through intercellular interactions. Remodeling of the brain immune microenvironment is regionally specific, stage dependent, and heterogeneous across cellular states; conventional pro-inflammatory/anti-inflammatory or activated/resting dichotomies therefore fail to capture its dynamics. This review examines the remodeling of the AD brain immune microenvironment through interactions among microglia, astrocytes, complement, and the neurovascular unit, with emphasis on their roles in Aβ and tau pathology, synaptic injury, lipid homeostasis, and vascular dysfunction, and considers the interpretive limits of single-cell and spatial-omics evidence. Current evidence supports a dynamically reconfigured system rather than a uniformly escalating inflammatory response. Therapeutic strategies should move beyond broad anti-inflammatory approaches to preserve effective pathological clearance within appropriate disease windows, limit maladaptive synaptic injury, and restore glial and neurovascular homeostasis.},
}

Humans
*Alzheimer Disease/immunology/pathology/metabolism
*Microglia/immunology/metabolism/pathology
*Astrocytes/immunology/metabolism/pathology
*Complement System Proteins/immunology/metabolism
*Brain/immunology/pathology/metabolism/blood supply
Animals
*Cellular Microenvironment/immunology
Amyloid beta-Peptides/metabolism

@article {pmid42866775,
year = {2026},
author = {Bhatia, V and Khatak, A},
title = {A positive Alzheimer's blood biomarker is not a diagnosis: the presence-primacy-permission framework for plasma p-tau217.},
journal = {Annals of medicine and surgery (2012)},
volume = {88},
number = {10},
pages = {6232-6234},
pmid = {42866775},
issn = {2049-0801},
abstract = {Validated plasma phosphorylated tau 217 (p-tau217) assays identify Alzheimer disease pathology with high accuracy. Wider clinical use creates a risk of postanalytic misclassification when pathology is converted directly into a clinical diagnosis or treatment decision. This editorial examines why accuracy relative to amyloid positron emission tomography or cerebrospinal fluid biomarkers does not establish that Alzheimer disease is the principal cause of a patient's cognitive syndrome. It describes three substitutions: pathology for diagnosis, presence for primacy, and diagnosis for treatment eligibility. We propose the presence-primacy-permission framework to distinguish confirmation of pathology from clinical-biological concordance and treatment suitability. Presence requires appropriate patient selection, a validated assay, and context-specific interpretation. Primacy requires integration of cognitive phenotype, trajectory, functional status, neurologic examination, structural imaging, and coexisting pathology. Permission requires assessment of clinical stage, hemorrhagic risk, treatment feasibility, and patient goals. Separate documentation of the biomarker result, syndrome, etiologic attribution, and actionability may reduce premature diagnostic closure while preserving the clinical value of p-tau217.},
}

@article {pmid42867612,
year = {2026},
author = {Fang, X and Border, JJ and Zhang, H and Morgan, GC and Gregory, A and Hanscom-Trofy, Y and Dong, R and Yang, J and Hwang, SH and Morisseau, C and Hammock, BD and Fan, F and Roman, RJ},
title = {Inhibition of soluble epoxide hydrolase rescues cognitive deficits by preserving neurovascular integrity and attenuating glial and neuropathology in diabetic-related dementia.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {42867612},
issn = {2509-2723},
support = {AG079336//NIH/ ; AG057842/AG/NIA NIH HHS/United States ; AG094068/AG/NIA NIH HHS/United States ; R35ES030443/ES/NIEHS NIH HHS/United States ; U54NS127758/NS/NINDS NIH HHS/United States ; A25-1690//Harrington Discovery Institute, University Hospitals/ ; 25PRE1365157//American Heart Association/ ; 25POST1363814//American Heart Association/ ; TRIBA/ Physiology Faculty Startup Fund//Augusta University/ ; },
abstract = {Diabetes mellitus (DM) is a major risk factor contributing to the development of Alzheimer's disease-related dementias (ADRD). While one of the early symptoms of both Alzheimer's disease (AD) and DM-related ADRD is a reduction in cerebral blood flow, the underlying biological mechanisms driving this decline remain to be fully elucidated. Genome-wide association studies have linked AD/ADRD to single-nucleotide polymorphisms in the gene encoding soluble epoxide hydrolase (sEH), an enzyme we previously reported to be upregulated in the brains of an AD rat model. Our previous studies also demonstrated that chronic sEH inhibition with 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU) preserves hippocampal-dependent spatial learning and memory and improves cerebral hemodynamics in both AD and DM-ADRD models. In the present study, we found that chronic TPPU treatment (1 mg/kg/day) reduced sEH expression in the brain, improved cortical-based non-spatial recognition memory involving both cortical and hippocampal networks, and reduced anxiety in DM-ADRD rats. TPPU improved brain perfusion and normalized impaired whisker-evoked functional hyperemia, an effect associated with increased Kir2.1 expression and neurovascular coupling in cerebral capillaries. Furthermore, TPPU increased tight junction protein expression (ZO-1 and OCLN), mitigated capillary rarefaction, and suppressed astrocyte and microglial activation in DM-ADRD rats. At the cellular level, TPPU attenuated hippocampal neurodegeneration, restored the expression of synaptic proteins (PSD95 and SY38), and reduced levels of proinflammatory chemokines, including MCP-1, RANTES, and MIP-1α, in the hippocampus of DM-ADRD rats. In conclusion, TPPU preserves cognitive function in DM-ADRD by mitigating cerebrovascular dysfunction, neuroinflammation and gliosis, thereby preserving synaptic integrity and neuronal survival, and represents a promising therapeutic strategy for DM-ADRD.},
}

@article {pmid42868046,
year = {2026},
author = {Lv, C and Luo, Q and Jin, F and Shao, Q and Qiu, Y and Ni, J and Liu, J and Qing, H and Quan, Z},
title = {Intermittent hypoxia training alleviates cerebral hypoperfusion and amyloid-β deposition in a mixed dementia model established by bilateral common carotid artery stenosis in early-stage 5xFAD mice.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261497235},
doi = {10.1177/13872877261497235},
pmid = {42868046},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is the most common form of dementia and often coexists with vascular pathology in clinical settings, resulting in mixed dementia with more severe symptoms and more rapid progression.ObjectiveTo investigate whether chronic cerebral hypoperfusion aggravates early AD-related pathology, we established a mixed dementia-like model by inducing bilateral common carotid artery stenosis (BCAS) in early-stage 5xFAD mice and evaluated the effects of intermittent hypoxia treatment (IHT).MethodsEarly-stage 5xFAD mice were subjected to BCAS to induce chronic cerebral hypoperfusion. Cognitive performance, cerebral perfusion, amyloid-β (Aβ) deposition, glial reactivity, tight-junction transcripts, and perivascular astrocyte-vascular organization were assessed. The therapeutic effects of IHT were then evaluated in this mixed dementia-like model.ResultsBCAS-induced hypoperfusion aggravated cognitive impairment in early-stage 5xFAD mice and accelerated pathological changes, including increased Aβ burden and stronger glial reactivity. These changes were accompanied by altered tight-junction transcripts and impaired perivascular astrocyte-vascular organization. IHT mitigated several features of the mixed dementia phenotype, including cerebral hypoperfusion, Aβ accumulation, glial reactivity, and altered perivascular AQP4/CD31 organization, while partially improving cognitive performance.ConclusionsChronic cerebral hypoperfusion can exacerbate early AD-related pathological and cognitive changes. IHT may alleviate mixed dementia-like phenotypes by improving cerebral perfusion, with accompanying changes in perivascular AQP4/CD31 organization and tight-junction transcripts.},
}

@article {pmid42869342,
year = {2026},
author = {Mikalauskaite, K and Veiveris, D and Smirnovas, V and Ziaunys, M},
title = {Effect of freeze-thaw cycle induced oligomers on alpha-synuclein liquid-liquid phase separation and aggregation.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {154845},
doi = {10.1016/j.ijbiomac.2026.154845},
pmid = {42869342},
issn = {1879-0003},
abstract = {Protein aggregation in the form of amyloid fibrils is linked with the onset and progression of several widespread and incurable disorders, including neurodegenerative Alzheimer's and Parkinson's diseases. Despite decades of research and countless attempts to discover potential aggregation-altering treatment modalities, there are still no effective cures for the majority of amyloid-related disorders. This is, in part, due to our incomplete understanding of the underlying factors that influence the phase separation and aggregation of these various disease-related proteins. Over the last few years, it has been shown that even factors such as storage conditions or sample preincubation times can affect the formation kinetics of amyloid fibrils. In the case of alpha-synuclein, even the protein purification procedure yielded different concentrations of oligomeric species, which altered the aggregation mechanism. In this work, we further explore the role of alpha-synuclein oligomers by inducing their formation via freeze-thaw cycles and analyzing their effect on liquid-liquid and liquid-solid phase transitions. Using real-time kinetic monitoring, brightfield microscopy, Fourier-transform infrared spectroscopy and atomic force microscopy, we show that the presence of freeze-thaw cycle induced alpha-synuclein oligomers has significant effects on its condensate assembly and subsequent aggregation, as well as the final structure of the formed aggregates.},
}

@article {pmid42869847,
year = {2026},
author = {Liu, X and de Boer, SCM and Tartaglia, MC and , },
title = {Sex-specific brain reserve and progression from mild cognitive impairment to Alzheimer's disease dementia.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {e71913},
doi = {10.1002/alz.71913},
pmid = {42869847},
issn = {1552-5279},
support = {//Donald Weaver Postdoctoral Fellowship/ ; //Early Career Grant of Alzheimer Nederland/ ; //Brain Canada-Krembil/ ; //Canadian Institute of Health Research/ ; //Tanenbaum Institute of Research in Sports Science/ ; //Weston Family Foundation/ ; //Michael J. Fox Foundation for Parkinson's Research/ ; },
mesh = {Humans ; Female ; *Alzheimer Disease/pathology/diagnostic imaging/cerebrospinal fluid ; *Cognitive Dysfunction/pathology/diagnostic imaging/cerebrospinal fluid ; Male ; Disease Progression ; *Brain/pathology/diagnostic imaging ; tau Proteins/metabolism ; Aged ; Positron-Emission Tomography ; *Sex Characteristics ; Magnetic Resonance Imaging ; Atrophy ; Longitudinal Studies ; Aged, 80 and over ; Gray Matter/pathology/diagnostic imaging ; Biomarkers/cerebrospinal fluid ; },
abstract = {INTRODUCTION: Sex differences exist in Alzheimer's disease (AD) treatment response, but the role of sex in disease development and progression remains unclear.

METHODS: We performed multimodal analyses of AD biomarker-positive individuals with mild cognitive impairment (MCI) and AD from the Alzheimer's Disease Neuroimaging Initiative (ADNI; MCI n = 593, AD n = 270) and National Alzheimer's Coordinating Center (MCI n = 436, AD n = 174). Baseline gray matter volume (GMV) was compared by sex. In ADNI, tau positron emission tomography burden and cerebrospinal fluid growth-associated protein 43 (GAP-43) were assessed. Longitudinal analyses examined atrophy and conversion from MCI to dementia.

RESULTS: Females with MCI exhibited greater baseline GMV than males primarily in the thalamus, caudate, cerebellum, postcentral gyrus, and middle cingulate gyrus, with no differences at the AD stage. Despite this, females exhibited higher baseline GAP-43, greater tau burden in temporal and parietal regions, and more rapid annual hippocampal atrophy. Conversion rates were similar.

DISCUSSION: Findings suggest that females may tolerate greater pathology at early stages but experience faster neurodegeneration later, supporting sex-specific disease trajectories and highlighting the need for sex-informed biomarkers.},
}

Humans
Female
*Alzheimer Disease/pathology/diagnostic imaging/cerebrospinal fluid
*Cognitive Dysfunction/pathology/diagnostic imaging/cerebrospinal fluid
Male
Disease Progression
*Brain/pathology/diagnostic imaging
tau Proteins/metabolism
Aged
Positron-Emission Tomography
*Sex Characteristics
Magnetic Resonance Imaging
Atrophy
Longitudinal Studies
Aged, 80 and over
Gray Matter/pathology/diagnostic imaging
Biomarkers/cerebrospinal fluid

@article {pmid42858079,
year = {2026},
author = {Yang, X and Ye, T and He, Y and Zhao, J and Wang, J and Cheng, X},
title = {Qi-Fu-Yin Attenuates Frailty by Regulating Gut Microbiota and Neuroendocrine Hormones in 5xFamilial Alzheimer's Disease Transgenic Mice.},
journal = {Journal of visualized experiments : JoVE},
volume = {},
number = {236},
pages = {},
doi = {10.3791/73003},
pmid = {42858079},
issn = {1940-087X},
mesh = {Animals ; *Alzheimer Disease/drug therapy/microbiology/blood/metabolism ; Mice, Transgenic ; Mice ; *Gastrointestinal Microbiome/drug effects ; *Drugs, Chinese Herbal/pharmacology/administration & dosage ; *Frailty/drug therapy/microbiology ; Female ; Male ; Disease Models, Animal ; },
abstract = {Frailty is a common and debilitating feature of Alzheimer's disease (AD), yet effective therapeutic strategies targeting both cognitive decline and physical frailty remain limited. Qi-Fu-Yin (QFY), a traditional Chinese herbal formulation, has been used to treat aging-related disorders, but its effects on frailty in AD and the underlying mechanisms are unclear. This study aimed to evaluate whether QFY alleviates frailty in 5xFamilial Alzheimer's Disease (FAD) transgenic mice and to explore the potential involvement of gut microbiota and neuroendocrine hormones. Mice were treated with QFY at low (2.8 g/kg), medium (5.6 g/kg), or high (11.2 g/kg) doses, or with donepezil as a positive control, for 194 days. Frailty-related behaviors were assessed using CatWalk gait analysis, grip strength, rotarod, nest-building, and aging scoring. Plasma hormone levels were measured, and fecal gut microbiota composition and function were analyzed by 16S rRNA sequencing and metagenomic analysis. QFY treatment significantly improved gait parameters, grip strength, motor coordination, nesting ability, and reduced aging scores in 5xFAD mice, with effects comparable to or superior to those of donepezil. QFY also restored aberrant levels of estradiol, testosterone, and corticosterone, and reshaped gut microbiota composition, particularly by increasing the abundance of Adlercreutzia, which negatively correlated with senescence and testosterone levels. Functional metagenomics revealed that QFY partially restored disease-associated microbial pathways, including those involved in carbohydrate metabolism and virulence. These findings suggest that QFY alleviates frailty in 5xFAD mice, with effects associated with concurrent modulation of gut microbiota and neuroendocrine function, though causal relationships require further validation. These findings support further investigation of QFY as a potential intervention for AD-associated frailty.},
}

Animals
*Alzheimer Disease/drug therapy/microbiology/blood/metabolism
Mice, Transgenic
Mice
*Gastrointestinal Microbiome/drug effects
*Drugs, Chinese Herbal/pharmacology/administration & dosage
*Frailty/drug therapy/microbiology
Female
Male
Disease Models, Animal

@article {pmid42858322,
year = {2026},
author = {Yang, Y and Zhang, X and Zan, X and Niu, C and Wei, X and Feng, P and Li, G and Gao, M},
title = {A Clearance-Repair-Activation Framework for Alzheimer's Disease: A Perspective and Validation Roadmap.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2026.1040},
pmid = {42858322},
issn = {2152-5250},
abstract = {Alzheimer's disease (AD) is a heterogeneous clinicobiological syndrome involving impaired protein clearance, neuroinflammation, synaptic and cellular injury, network dysfunction, and progressive functional decline. Amyloid-directed antibodies provide an evidence-based treatment backbone for selected patients with early symptomatic AD, but adjunctive strategies may be needed to address other disease mechanisms. This Perspective proposes a clearance-repair-activation framework for hypothesis-driven research. Clearance includes established pharmacological treatment and risk management as well as investigational drainage approaches; lymphaticovenous anastomosis (LVA) and deep cervical lymphaticovenous anastomosis (dcLVA) are considered only as research options within this broader domain. Repair includes neural stem-cell (NSC), induced pluripotent stem-cell-derived, engineered-cell, and secretome-based strategies, for which AD evidence remains predominantly preclinical. Activation encompasses invasive and non-invasive stimulation, sensory entrainment, neurofeedback, brain-computer interface (BCI) monitoring, and cognitive rehabilitation; BCI is positioned mainly as an experimental monitoring and adaptive rehabilitation platform. We define falsifiable links between clearance and repair readiness and between repair markers and activation responsiveness, consider adaptive and parallel alternatives to fixed sequencing, and integrate disease stage, heterogeneity, regulation, and combination-trial design. Informatics is limited to trial infrastructure and safety governance. The validation roadmap specifies success criteria, stop rules, interaction testing, clinically meaningful outcomes, and long-term surveillance.},
}

@article {pmid42858330,
year = {2026},
author = {Zhang, K and Zhang, Y and Jiang, X and Chen, X},
title = {Neuroimmune State Configurations at the Amyloid-Tau Interface in Alzheimer's Disease: A Testable Framework.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2026.0888},
pmid = {42858330},
issn = {2152-5250},
abstract = {Neuroimmune mechanisms are central to Alzheimer's disease (AD), but a single continuum of "more inflammation" does not explain why similar amyloid-β (Aβ) and tau burdens are associated with different clinical trajectories, tissue responses, and treatment risks. We present a testable neuroimmune-state framework that integrates, rather than replaces, the AT(N) system, cellular-phase models, and transcriptional descriptions of disease-associated microglia and reactive astrocytes. The framework treats neuroimmune states as multidimensional, regionally heterogeneous configurations defined by pathological substrate, cellular program, biological target, vascular and aging context, and measurable patient-level readouts. We distinguish four meanings of the amyloid-tau interface: a biomarker interface, a spatial tissue interface, a cellular-state interface, and a clinical-progression interface. We then examine the hypothesis of phagocytic target switching, in which clearance pathways that support plaque compaction or debris removal may, under selected tau- and complement-rich conditions, contribute to removal of stressed but potentially functional synapses. We explicitly separate evidence from longitudinal human studies, cross-sectional biomarkers, human genetics, postmortem tissue, animal models, and in vitro systems. Current biomarkers cannot yet assign patients to validated discrete neuroimmune states; proposed state readers should therefore be probabilistic, allow regional coexistence and parallel vascular-immune trajectories, and be tested for incremental value beyond established AD biomarkers and co-pathologies. Finally, we organize immune-directed interventions by clinical evidence level and frame stage matching as a research strategy rather than a treatment algorithm. The model is useful only if its predictions can be prospectively supported or falsified.},
}

@article {pmid42858944,
year = {2026},
author = {Patel, DR and Rangasamy, SB and Gorai, S and Paidi, RK and Pahan, K},
title = {Glyceryl tribenzoate, a flavoring agent, stimulates hippocampal plasticity and protects memory via PPARα.},
journal = {Neurochemistry international},
volume = {201},
number = {},
pages = {106270},
doi = {10.1016/j.neuint.2026.106270},
pmid = {42858944},
issn = {1872-9754},
abstract = {Glyceryl tribenzoate (GTB) or tribenzoin is a flavoring agent with characteristic anti-microbial property. We have already delineated GTB's immunomodulatory role via the enrichment of regulatory T cells in mouse models of multiple sclerosis and anti-neuroinflammatory role via the reduction of glial activation in a monkey model of Parkinson's disease and a mouse model of Huntington's disease. However, its role has never been explored in Alzheimer's disease (AD), the most common neurodegenerative disorder in human. This study underlines the importance of GTB in promoting the growth and function of hippocampal neurons via upregulation of plasticity-associated genes, enrichment of dendritic spines and stimulation of inotropic calcium influx. Accordingly, oral GTB improved hippocampal plasticity and protected memory and learning in 5xFAD mice. Similarly, GTB treatment also reduced cerebral plaque load and increased the life span of aged 5xFAD mice. Interestingly, we observed that peroxisome proliferator-activated receptor alpha (PPARα), a nuclear hormone receptor, served as a receptor of GTB. Consequently, GTB was shown to improve hippocampal plasticity and increase cognitive functions in 5xFAD, but not 5xFAD/Ppara-null, mice, indicating an important role of PPARα in GTB-mediated neuroprotection. These results suggest that oral GTB may have therapeutic importance for improving hippocampal functions in AD patients.},
}